6S8A

Crystal Structure of EGFR-T790M/C797S in Complex with Covalent Pyrrolopyrimidine 19h

External Resource: Annotation

Domain Annotation: SCOP/SCOPe Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations

Domain Annotation: SCOP/SCOPe Classification SCOP-e Database Homepage

Chains	Domain Info	Class	Fold	Superfamily	Family	Domain	Species	Provenance Source (Version)
A	d6s8aa_	Alpha and beta proteins (a+b)	Protein kinase-like (PK-like)	Protein kinase-like (PK-like)	Protein kinases, catalytic subunit	EGF receptor tyrosine kinase, Erbb-1	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	Pkinase_Tyr	e6s8aA1	A: a+b complex topology	X: Protein kinase/SAICAR synthase/ATP-grasp (From Homology)	H: Protein kinase/SAICAR synthase/ATP-grasp	T: Protein kinase	F: Pkinase_Tyr	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	3.30.200.20	Alpha Beta	2-Layer Sandwich	Phosphorylase Kinase	domain 1	CATH (utative)
A	1.10.510.10	Mainly Alpha	Orthogonal Bundle	Transferase(Phosphotransferase)	domain 1	CATH (utative)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A	PF07714	Protein tyrosine and serine/threonine kinase (PK_Tyr_Ser-Thr)	Protein tyrosine and serine/threonine kinase	Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosph ...	Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [1]; Serine/threonine-protein kinases, tyrosine-protein kinases, and dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins). This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include the catalytic domain of dual specificity kinases.	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A	Epidermal growth factor receptor	cytoskeletal protein binding actin binding protein-containing complex binding protein binding binding actin filament binding protein phosphatase binding phosphatase binding enzyme binding protein tyrosine kinase activity catalytic activity, acting on a protein kinase activity protein kinase activity transferase activity cytoskeletal protein binding actin binding protein-containing complex binding protein binding binding actin filament binding protein phosphatase binding phosphatase binding enzyme binding protein tyrosine kinase activity catalytic activity, acting on a protein kinase activity protein kinase activity transferase activity catalytic activity phosphotransferase activity, alcohol group as acceptor transferase activity, transferring phosphorus-containing groups adenyl ribonucleotide binding nucleotide binding purine ribonucleotide binding purine ribonucleoside triphosphate binding nucleoside phosphate binding ion binding purine nucleotide binding organic cyclic compound binding anion binding adenyl nucleotide binding ATP binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding small molecule binding cell adhesion molecule binding cadherin binding calmodulin binding ubiquitin protein ligase binding ubiquitin-like protein ligase binding growth factor binding epidermal growth factor binding hormone binding molecular transducer activity transmembrane signaling receptor activity signaling receptor activity protein tyrosine kinase activator activity enzyme regulator activity transmembrane receptor protein tyrosine kinase activator activity molecular function activator activity protein kinase regulator activity signaling receptor activator activity kinase activator activity enzyme activator activity molecular function regulator activity signaling receptor regulator activity protein kinase activator activity kinase regulator activity kinase binding protein kinase binding protein serine/threonine kinase activity MAP kinase kinase kinase activity transmembrane receptor protein tyrosine kinase activity transmembrane receptor protein kinase activity ATPase binding identical protein binding virus receptor activity exogenous protein binding epidermal growth factor receptor activity chromatin binding integrin binding signaling receptor binding DNA binding double-stranded DNA binding nucleic acid binding	developmental process multicellular organismal process gland development animal organ development salivary gland development anatomical structure morphogenesis multicellular organism development gland morphogenesis salivary gland morphogenesis anatomical structure development animal organ morphogenesis exocrine system development system development regulation of biological process developmental process multicellular organismal process gland development animal organ development salivary gland development anatomical structure morphogenesis multicellular organism development gland morphogenesis salivary gland morphogenesis anatomical structure development animal organ morphogenesis exocrine system development system development regulation of biological process regulation of cellular process reactive oxygen species metabolic process biological regulation positive regulation of biological process regulation of superoxide metabolic process positive regulation of reactive oxygen species metabolic process superoxide metabolic process positive regulation of metabolic process superoxide anion generation metabolic process cellular process positive regulation of superoxide anion generation regulation of superoxide anion generation regulation of metabolic process regulation of reactive oxygen species metabolic process positive regulation of cellular process regulation of tube diameter system process regulation of tube size regulation of system process positive regulation of vasoconstriction circulatory system process regulation of blood circulation vascular process in circulatory system regulation of vasoconstriction positive regulation of multicellular organismal process regulation of multicellular organismal process blood vessel diameter maintenance regulation of biological quality vasoconstriction blood circulation regulation of anatomical structure size tongue development sensory organ development positive regulation of protein localization to plasma membrane protein localization regulation of localization cellular localization regulation of protein localization localization cellular macromolecule localization regulation of protein localization to membrane positive regulation of protein localization to cell periphery protein localization to cell periphery protein localization to plasma membrane positive regulation of protein localization to membrane localization within membrane regulation of protein localization to cell periphery protein localization to membrane regulation of cellular localization macromolecule localization positive regulation of protein localization regulation of protein localization to plasma membrane positive regulation of phosphorylation regulation of protein modification process regulation of protein phosphorylation positive regulation of protein metabolic process regulation of peptidyl-serine phosphorylation positive regulation of phosphate metabolic process peptidyl-serine modification regulation of primary metabolic process positive regulation of protein modification process peptidyl-serine phosphorylation regulation of phosphate metabolic process phosphate-containing compound metabolic process peptidyl-amino acid modification positive regulation of macromolecule metabolic process protein metabolic process positive regulation of protein phosphorylation phosphorus metabolic process protein modification process protein phosphorylation positive regulation of phosphorus metabolic process phosphorylation regulation of protein metabolic process primary metabolic process regulation of macromolecule metabolic process positive regulation of peptidyl-serine phosphorylation macromolecule modification regulation of phosphorus metabolic process regulation of phosphorylation macromolecule metabolic process cerebral cortex cell migration head development forebrain development brain development nervous system development pallium development cerebral cortex development telencephalon cell migration central nervous system development forebrain cell migration cell migration telencephalon development cell motility cellular response to stimulus response to stimulus signaling negative regulation of signaling negative regulation of ERBB signaling pathway negative regulation of biological process regulation of signal transduction cell surface receptor protein tyrosine kinase signaling pathway negative regulation of cell communication cell communication regulation of epidermal growth factor receptor signaling pathway negative regulation of cellular process epidermal growth factor receptor signaling pathway signal transduction enzyme-linked receptor protein signaling pathway regulation of signaling regulation of ERBB signaling pathway cell surface receptor signaling pathway negative regulation of response to stimulus negative regulation of signal transduction regulation of response to stimulus negative regulation of epidermal growth factor receptor signaling pathway ERBB signaling pathway regulation of cell communication regulation of cellular response to stress positive regulation of response to stimulus nucleobase-containing compound metabolic process positive regulation of DNA repair cellular response to stress response to stress regulation of response to stress regulation of nucleobase-containing compound metabolic process DNA repair positive regulation of nucleobase-containing compound metabolic process DNA metabolic process nucleic acid metabolic process regulation of DNA repair positive regulation of DNA metabolic process DNA damage response regulation of DNA metabolic process positive regulation of DNA-templated transcription RNA metabolic process positive regulation of miRNA transcription positive regulation of miRNA metabolic process positive regulation of macromolecule biosynthetic process RNA biosynthetic process DNA-templated transcription nucleic acid biosynthetic process regulation of RNA metabolic process miRNA transcription positive regulation of biosynthetic process regulation of miRNA metabolic process miRNA metabolic process regulation of RNA biosynthetic process regulation of biosynthetic process nucleobase-containing compound biosynthetic process gene expression macromolecule biosynthetic process positive regulation of RNA metabolic process regulation of gene expression biosynthetic process positive regulation of RNA biosynthetic process regulation of macromolecule biosynthetic process regulation of DNA-templated transcription regulation of miRNA transcription response to nutrient levels response to cobalamin response to chemical response to nutrient response to oxygen-containing compound response to nitrogen compound response to vitamin response to organic cyclic compound cellular developmental process astrocyte differentiation cell development astrocyte activation glial cell development neurogenesis astrocyte development gliogenesis cell differentiation defense response cell activation glial cell differentiation glial cell activation inflammatory response neuroinflammatory response ossification cell population proliferation regulation of smooth muscle cell proliferation positive regulation of cell population proliferation smooth muscle cell proliferation positive regulation of smooth muscle cell proliferation regulation of cell population proliferation muscle cell proliferation digestive system development tube development digestive tract development tube morphogenesis digestive tract morphogenesis positive regulation of cell communication establishment of protein localization nitrogen compound transport positive regulation of establishment of protein localization regulation of peptide hormone secretion positive regulation of prolactin secretion regulation of hormone levels positive regulation of peptide hormone secretion establishment of protein localization to extracellular region protein secretion establishment of localization regulation of secretion regulation of protein secretion regulation of hormone secretion regulation of peptide secretion transport positive regulation of secretion by cell hormone secretion protein localization to extracellular region positive regulation of protein transport peptide secretion secretion by cell regulation of secretion by cell positive regulation of hormone secretion positive regulation of secretion amide transport signal release positive regulation of peptide secretion secretion regulation of transport regulation of peptide transport regulation of establishment of protein localization prolactin secretion cell-cell signaling export from cell regulation of protein transport positive regulation of protein secretion peptide transport positive regulation of transport protein transport peptide hormone secretion hormone transport positive regulation of signaling cellular response to chemical stimulus cellular response to xenobiotic stimulus response to xenobiotic stimulus ERBB2 signaling pathway ERBB2-EGFR signaling pathway ovulation cycle rhythmic process reproductive process multicellular organismal reproductive process regulation of growth regulation of cellular component organization growth positive regulation of cell growth regulation of cell growth cell growth cellular component organization positive regulation of growth cellular component organization or biogenesis circadian rhythm hydrogen peroxide metabolic process positive regulation of signal transduction intracellular signal transduction positive regulation of ERK1 and ERK2 cascade regulation of intracellular signal transduction intracellular signaling cassette positive regulation of MAPK cascade positive regulation of intracellular signal transduction regulation of MAPK cascade MAPK cascade ERK1 and ERK2 cascade regulation of ERK1 and ERK2 cascade modulation of chemical synaptic transmission synaptic transmission, glutamatergic regulation of synaptic transmission, glutamatergic synaptic signaling trans-synaptic signaling positive regulation of synaptic transmission positive regulation of synaptic transmission, glutamatergic chemical synaptic transmission regulation of trans-synaptic signaling anterograde trans-synaptic signaling negative regulation of programmed cell death regulation of apoptotic process regulation of programmed cell death cell death negative regulation of apoptotic process apoptotic process programmed cell death epithelium development epidermis development molting cycle process hair cycle tissue development skin development skin epidermis development hair follicle development molting cycle hair cycle process morphogenesis of an epithelial fold tissue morphogenesis morphogenesis of an epithelium animal organ regeneration liver development regeneration hepaticobiliary system development liver regeneration regulation of catalytic activity regulation of cyclin-dependent protein kinase activity regulation of transferase activity positive regulation of protein serine/threonine kinase activity positive regulation of cyclin-dependent protein serine/threonine kinase activity regulation of cyclin-dependent protein serine/threonine kinase activity cell cycle regulation of molecular function positive regulation of kinase activity regulation of kinase activity regulation of protein serine/threonine kinase activity positive regulation of cyclin-dependent protein kinase activity positive regulation of molecular function positive regulation of protein kinase activity regulation of cell cycle positive regulation of transferase activity positive regulation of catalytic activity regulation of protein kinase activity positive regulation of cell cycle placenta development chordate embryonic development embryo development in utero embryonic development embryonic placenta development embryo development ending in birth or egg hatching embryonic organ development epithelial cell proliferation response to mechanical stimulus response to external stimulus response to abiotic stimulus cellular response to mechanical stimulus cellular response to abiotic stimulus cellular response to external stimulus cellular response to environmental stimulus positive regulation of locomotion regulation of cell motility positive regulation of cell migration regulation of locomotion positive regulation of cell motility regulation of cell migration locomotion regulation of body fluid levels secretion by tissue regulation of mucus secretion mucus secretion body fluid secretion positive regulation of mucus secretion response to lipid cellular response to organic cyclic compound cellular response to oxygen-containing compound cellular response to lipid response to estradiol cellular response to estradiol stimulus membrane organization establishment of protein localization to membrane protein insertion into membrane regulation of canonical Wnt signaling pathway canonical Wnt signaling pathway positive regulation of Wnt signaling pathway Wnt signaling pathway positive regulation of canonical Wnt signaling pathway regulation of Wnt signaling pathway eyelid development in camera-type eye eye development visual system development camera-type eye development sensory system development cellular response to endogenous stimulus cellular response to growth factor stimulus response to endogenous stimulus cellular response to epidermal growth factor stimulus response to epidermal growth factor response to growth factor positive regulation of nervous system development regulation of developmental process regulation of neurogenesis regulation of cell differentiation regulation of gliogenesis positive regulation of glial cell proliferation positive regulation of gliogenesis regulation of cell development regulation of nervous system development positive regulation of developmental process regulation of glial cell proliferation positive regulation of cell differentiation positive regulation of neurogenesis regulation of multicellular organismal development positive regulation of cell development glial cell proliferation response to oxidative stress protein autophosphorylation peptidyl-tyrosine modification peptidyl-tyrosine autophosphorylation peptidyl-tyrosine phosphorylation midgut development response to metal ion response to calcium ion regulation of peptidyl-tyrosine phosphorylation positive regulation of DNA replication DNA replication regulation of DNA replication response to ketone response to hormone response to steroid hormone cellular response to ketone cellular response to steroid hormone stimulus cellular response to hormone stimulus cellular response to dexamethasone stimulus response to glucocorticoid cellular response to glucocorticoid stimulus cellular response to corticosteroid stimulus response to corticosteroid response to dexamethasone regulation of cell cycle phase transition cell cycle phase transition regulation of cell cycle G1/S phase transition cell cycle G1/S phase transition mitotic cell cycle regulation of mitotic cell cycle positive regulation of mitotic cell cycle phase transition positive regulation of cell cycle process positive regulation of mitotic cell cycle cell cycle process positive regulation of G1/S transition of mitotic cell cycle regulation of cell cycle process regulation of mitotic cell cycle phase transition positive regulation of cell cycle G1/S phase transition mitotic cell cycle process regulation of G1/S transition of mitotic cell cycle positive regulation of cell cycle phase transition G1/S transition of mitotic cell cycle mitotic cell cycle phase transition response to light stimulus response to radiation response to UV response to UV-A cellular response to acid chemical cellular response to amino acid stimulus response to acid chemical response to amino acid homeostatic process regulation of bone remodeling tissue homeostasis regulation of tissue remodeling regulation of bone resorption bone resorption multicellular organismal-level homeostasis tissue remodeling bone remodeling anatomical structure homeostasis positive regulation of bone resorption catabolic process macromolecule catabolic process negative regulation of protein catabolic process negative regulation of protein metabolic process negative regulation of macromolecule metabolic process negative regulation of catabolic process negative regulation of metabolic process protein catabolic process regulation of catabolic process regulation of protein catabolic process transcription by RNA polymerase II regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II response to phenylpropanoid response to hydroxyisoflavone translation negative regulation of cell differentiation negative regulation of cardiocyte differentiation heart development negative regulation of developmental process cardiocyte differentiation circulatory system development regulation of cardiocyte differentiation negative regulation of multicellular organismal process fibroblast proliferation regulation of fibroblast proliferation positive regulation of fibroblast proliferation respiratory tube development lung development respiratory system development positive regulation of epithelial cell proliferation regulation of epithelial cell proliferation regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction phosphatidylinositol 3-kinase/protein kinase B signal transduction diterpenoid metabolic process terpenoid metabolic process isoprenoid metabolic process lipid metabolic process cell projection organization plasma membrane bounded cell projection morphogenesis neuron projection development cell morphogenesis cell projection morphogenesis neuron differentiation neuron projection morphogenesis plasma membrane bounded cell projection organization generation of neurons neuron development vasodilation behavior learning or memory nervous system process cognition cell adhesion cell-cell adhesion positive regulation of protein kinase C activity regulation of protein kinase C activity negative regulation of cell cycle negative regulation of mitotic cell cycle	membrane-bounded organelle intracellular anatomical structure nuclear membrane membrane nucleus intracellular membrane-bounded organelle endomembrane system intracellular organelle organelle envelope cellular anatomical structure organelle nuclear envelope organelle membrane intracellular vesicle membrane-bounded organelle intracellular anatomical structure nuclear membrane membrane nucleus intracellular membrane-bounded organelle endomembrane system intracellular organelle organelle envelope cellular anatomical structure organelle nuclear envelope organelle membrane intracellular vesicle bounding membrane of organelle cytoplasmic vesicle vesicle membrane clathrin-coated vesicle endocytic vesicle membrane coated vesicle vesicle endocytic vesicle clathrin-coated vesicle membrane clathrin-coated endocytic vesicle membrane clathrin-coated endocytic vesicle cytoplasmic vesicle membrane coated vesicle membrane cytoplasm protein-containing complex receptor complex Golgi membrane Golgi apparatus endosome membrane endosome extracellular region extracellular space anchoring junction cell junction focal adhesion cell-substrate junction cell periphery plasma membrane synapse plasma membrane region synaptic membrane apical part of cell apical plasma membrane ruffle cell leading edge leading edge membrane plasma membrane bounded cell projection cell projection ruffle membrane cell projection membrane basal part of cell basal plasma membrane cell surface membrane microdomain membrane raft organelle subcompartment endoplasmic reticulum subcompartment nuclear outer membrane-endoplasmic reticulum membrane network endoplasmic reticulum endoplasmic reticulum membrane basolateral plasma membrane glutamatergic synapse perinuclear region of cytoplasm Shc-EGFR complex plasma membrane protein complex membrane protein complex multivesicular body, internal vesicle vesicle lumen multivesicular body, internal vesicle lumen membrane-enclosed lumen intracellular organelle lumen organelle lumen late endosome multivesicular body early endosome early endosome membrane

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A	IPR016245	Tyrosine protein kinase, EGF/ERB/XmrK receptor	Family
A	IPR020635	Tyrosine-protein kinase, catalytic domain	Domain
A	IPR000719	Protein kinase domain	Domain
A	IPR032778	Growth factor receptor domain 4	Domain
A	IPR006212	Furin-like repeat	Repeat
A	IPR017441	Protein kinase, ATP binding site	Binding Site
A	IPR001245	Serine-threonine/tyrosine-protein kinase, catalytic domain	Domain
A	IPR009030	Growth factor receptor cysteine-rich domain superfamily	Homologous Superfamily
A	IPR008266	Tyrosine-protein kinase, active site	Active Site
A	IPR036941	Receptor L-domain superfamily	Homologous Superfamily
A	IPR049328	Epidermal growth factor receptor-like, transmembrane-juxtamembrane segment	Domain
A	IPR000494	Receptor L-domain	Domain
A	IPR011009	Protein kinase-like domain superfamily	Homologous Superfamily
A	IPR006211	Furin-like cysteine-rich domain	Domain
A	IPR050122	Receptor Tyrosine Kinase	Family

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A	Pharos: P00533	non-small cell lung carcinoma glioblastoma inflammatory skin and bowel disease, neonatal, 2 giant cell glioblastoma osteosarcoma lung cancer cholangiocarcinoma squamous cell carcinoma autosomal recessive polycystic kidney disease dilated cardiomyopathy breast cancer cancer esophageal squamous cell carcinoma classic familial adenomatous polyposis gliosarcoma non-small cell lung carcinoma glioblastoma inflammatory skin and bowel disease, neonatal, 2 giant cell glioblastoma osteosarcoma lung cancer cholangiocarcinoma squamous cell carcinoma autosomal recessive polycystic kidney disease dilated cardiomyopathy breast cancer cancer esophageal squamous cell carcinoma classic familial adenomatous polyposis gliosarcoma breast carcinoma malignant colon neoplasm ovarian cancer papilloma urinary bladder cancer adrenal cortex carcinoma squamous papilloma head and neck cancer tubular adenocarcinoma dermatitis head and neck squamous cell carcinoma Mammary Neoplasms, Experimental prostate cancer adenocarcinoma rectal cancer cervical cancer small cell lung carcinoma colorectal cancer malignant mesothelioma bile duct cancer type 2 diabetes mellitus intrahepatic cholangiocarcinoma gallbladder cancer granular cell carcinoma bile duct carcinoma endometriosis carcinoma esophageal cancer rectal neoplasm sarcomatoid carcinoma nasopharyngeal carcinoma malignant glioma cribriform carcinoma ovarian disease benign neoplasm of esophagus pancreatic ductal adenocarcinoma bile duct neoplasm malignant pancreatic neoplasm papillomatosis hepatocellular carcinoma brain disease urinary bladder disease pituitary cancer interstitial cystitis uterine disease endometrial carcinoma acute kidney failure kidney disease maturity-onset diabetes of the young endometrium adenocarcinoma laryngeal squamous cell carcinoma carcinoma of esophagus rheumatoid arthritis lung benign neoplasm nasopharyngeal neoplasm lung disease neoplasm of esophagus gastric cancer major depressive disorder atypical teratoid rhabdoid tumor squamous cell lung carcinoma Cowden syndrome 1 benign colon neoplasm subependymal giant cell astrocytoma cribriform carcinoma of breast ovarian neoplasm head and neck carcinoma pancreatic neoplasm bone disease malignant tumor of nasopharynx dilated cardiomyopathy 1A Pick disease brain glioma urinary bladder neoplasm ductal breast carcinoma in situ prostate disease medulloblastoma endometrium carcinoma in situ rectal carcinoma myopathy esophagus carcinoma in situ adrenal carcinoma sarcoidosis small cell carcinoma alcohol abuse spina bifida colonic neoplasm neoplasm of neck gastric neoplasm colorectal carcinoma autosomal dominant polycystic kidney disease benign mesothelioma tongue squamous cell carcinoma cutaneous lupus erythematosus pancreatic adenocarcinoma head and neck neoplasm undifferentiated carcinoma digestive system disease hematologic disease hereditary diffuse gastric adenocarcinoma bone osteosarcoma malignant tumor of neck pilocytic astrocytoma mammary neoplasms, animal prostate adenocarcinoma invasive ductal breast carcinoma breast disease large cell medulloblastoma mesothelioma lung adenocarcinoma exanthem lung carcinoma gallbladder neoplasm lymphatic system disease colorectal adenocarcinoma genetic intestinal polyposis astrocytic tumor oligodendroglioma glioma

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.