2G49

Crystal structure of human insulin-degrading enzyme in complex with glucagon

External Resource: Annotation

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

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	Peptidase_M16_M_C	e2g49A11	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16_M_C	ECOD (1.6)
A	Peptidase_M16_M_N	e2g49A12	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16_M_N	ECOD (1.6)
A	Peptidase_M16_C_2	e2g49A13	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16_C_2	ECOD (1.6)
A	Peptidase_M16	e2g49A4	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16	ECOD (1.6)
B	Peptidase_M16_M_C	e2g49B11	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16_M_C	ECOD (1.6)
B	Peptidase_M16_M_N	e2g49B12	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16_M_N	ECOD (1.6)
B	Peptidase_M16_C_2	e2g49B13	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16_C_2	ECOD (1.6)
B	Peptidase_M16	e2g49B4	A: a+b two layers	X: LuxS, MPP, ThrRS/AlaRS common domain	H: LuxS, MPP, ThrRS/AlaRS common domain	T: LuxS/MPP-like metallohydrolase	F: Peptidase_M16	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	3.30.830.10	Alpha Beta	2-Layer Sandwich	Cytochrome Bc1 Complex	Chain A, domain 1	CATH (4.3.0)
B	3.30.830.10	Alpha Beta	2-Layer Sandwich	Cytochrome Bc1 Complex	Chain A, domain 1	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B	PF05193	Peptidase M16 inactive domain (Peptidase_M16_C)	Peptidase M16 inactive domain	Peptidase M16 consists of two structurally related domains. One is the active peptidase, whereas the other is inactive. The two domains hold the substrate like a clamp [1].	Domain
A, B	PF16187	Middle or third domain of peptidase_M16 (Peptidase_M16_M)	Middle or third domain of peptidase_M16	-	Family
A, B	PF00675	Insulinase (Peptidase family M16) (Peptidase_M16)	Insulinase (Peptidase family M16)	-	Family
C, D	PF00123	Peptide hormone (Hormone_2)	Peptide hormone	-	Family

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B	Insulin-degrading enzyme	protein binding binding virus receptor activity exogenous protein binding amide binding peptide hormone binding hormone binding insulin binding peptidase activity catalytic activity, acting on a protein metalloendopeptidase activity hydrolase activity metallopeptidase activity catalytic activity protein binding binding virus receptor activity exogenous protein binding amide binding peptide hormone binding hormone binding insulin binding peptidase activity catalytic activity, acting on a protein metalloendopeptidase activity hydrolase activity metallopeptidase activity catalytic activity endopeptidase activity 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 identical protein binding protein homodimerization activity protein dimerization activity peptide binding cation binding transition metal ion binding zinc ion binding metal ion binding	amyloid-beta metabolic process metabolic process cellular process amide metabolic process cellular catabolic process catabolic process peptide metabolic process peptide catabolic process multicellular organismal process amyloid-beta clearance by cellular catabolic process amyloid-beta clearance primary metabolic process protein metabolic process macromolecule metabolic process amyloid-beta metabolic process metabolic process cellular process amide metabolic process cellular catabolic process catabolic process peptide metabolic process peptide catabolic process multicellular organismal process amyloid-beta clearance by cellular catabolic process amyloid-beta clearance primary metabolic process protein metabolic process macromolecule metabolic process insulin metabolic process protein catabolic process macromolecule catabolic process proteolysis involved in protein catabolic process proteolysis regulation of cellular process positive regulation of protein metabolic process positive regulation of biological process regulation of primary metabolic process positive regulation of metabolic process positive regulation of macromolecule metabolic process positive regulation of cellular process regulation of biological process regulation of protein metabolic process biological regulation regulation of macromolecule metabolic process regulation of catabolic process positive regulation of protein catabolic process positive regulation of catabolic process regulation of metabolic process regulation of protein catabolic process cellular homeostasis homeostatic process ubiquitin recycling cellular response to nitrogen compound cellular response to stimulus response to stimulus signaling response to peptide hormone insulin receptor signaling pathway cell surface receptor protein tyrosine kinase signaling pathway cell communication cellular response to endogenous stimulus response to hormone signal transduction enzyme-linked receptor protein signaling pathway cellular response to hormone stimulus cell surface receptor signaling pathway response to endogenous stimulus response to oxygen-containing compound cellular response to peptide hormone stimulus response to nitrogen compound cellular response to oxygen-containing compound cellular response to chemical stimulus response to chemical response to insulin cellular response to insulin stimulus antigen processing and presentation immune system process antigen processing and presentation of endogenous peptide antigen antigen processing and presentation of peptide antigen via MHC class I antigen processing and presentation of peptide antigen antigen processing and presentation of endogenous antigen antigen processing and presentation of endogenous peptide antigen via MHC class I regulation of hormone levels regulation of biological quality hormone metabolic process hormone catabolic process bradykinin catabolic process aerobic respiration cellular respiration energy derivation by oxidation of organic compounds regulation of generation of precursor metabolites and energy generation of precursor metabolites and energy regulation of cellular respiration regulation of aerobic respiration regulation of protein binding positive regulation of molecular function regulation of molecular function positive regulation of protein binding regulation of binding positive regulation of binding insulin catabolic process	membrane-bounded organelle intracellular organelle cellular anatomical structure intracellular anatomical structure mitochondrion organelle cytoplasm intracellular membrane-bounded organelle cell periphery cell surface membrane plasma membrane external side of plasma membrane side of membrane membrane-bounded organelle intracellular organelle cellular anatomical structure intracellular anatomical structure mitochondrion organelle cytoplasm intracellular membrane-bounded organelle cell periphery cell surface membrane plasma membrane external side of plasma membrane side of membrane extracellular exosome extracellular vesicle extracellular organelle extracellular region extracellular space vesicle extracellular membrane-bounded organelle cytosol basal part of cell basal plasma membrane plasma membrane region basolateral plasma membrane peroxisome microbody peroxisomal matrix membrane-enclosed lumen intracellular organelle lumen organelle lumen microbody lumen nucleus
C, D	glucagon preproprotein	protein binding binding signaling receptor binding molecular function activator activity molecular function regulator activity signaling receptor regulator activity receptor ligand activity signaling receptor activator activity G protein-coupled receptor binding glucagon receptor binding hormone activity identical protein binding	monosaccharide metabolic process regulation of cellular process positive regulation of biological process gluconeogenesis regulation of primary metabolic process positive regulation of metabolic process regulation of small molecule metabolic process positive regulation of biosynthetic process small molecule metabolic process regulation of carbohydrate metabolic process regulation of glucose metabolic process positive regulation of cellular process positive regulation of gluconeogenesis regulation of biosynthetic process monosaccharide metabolic process regulation of cellular process positive regulation of biological process gluconeogenesis regulation of primary metabolic process positive regulation of metabolic process regulation of small molecule metabolic process positive regulation of biosynthetic process small molecule metabolic process regulation of carbohydrate metabolic process regulation of glucose metabolic process positive regulation of cellular process positive regulation of gluconeogenesis regulation of biosynthetic process carbohydrate metabolic process regulation of biological process small molecule biosynthetic process carbohydrate biosynthetic process biological regulation hexose metabolic process primary metabolic process monosaccharide biosynthetic process hexose biosynthetic process positive regulation of glucose metabolic process biosynthetic process regulation of gluconeogenesis metabolic process cellular process positive regulation of carbohydrate metabolic process regulation of carbohydrate biosynthetic process positive regulation of small molecule metabolic process regulation of metabolic process glucose metabolic process cellular response to stimulus positive regulation of cell communication positive regulation of signal transduction response to stimulus signaling regulation of signal transduction intracellular signal transduction cell communication positive regulation of response to stimulus positive regulation of ERK1 and ERK2 cascade regulation of intracellular signal transduction intracellular signaling cassette signal transduction regulation of signaling positive regulation of MAPK cascade positive regulation of intracellular signal transduction regulation of MAPK cascade regulation of response to stimulus MAPK cascade regulation of cell communication ERK1 and ERK2 cascade regulation of ERK1 and ERK2 cascade positive regulation of signaling negative regulation of programmed cell death regulation of apoptotic process negative regulation of biological process regulation of programmed cell death cell death negative regulation of apoptotic process negative regulation of cellular process apoptotic process programmed cell death positive regulation of phosphorylation regulation of protein modification process regulation of protein phosphorylation positive regulation of protein metabolic process regulation of peptidyl-threonine phosphorylation positive regulation of phosphate metabolic process positive regulation of protein modification process regulation of phosphate metabolic process phosphate-containing compound metabolic process peptidyl-amino acid modification positive regulation of macromolecule metabolic process protein metabolic process peptidyl-threonine modification positive regulation of protein phosphorylation phosphorus metabolic process protein modification process protein phosphorylation positive regulation of phosphorus metabolic process positive regulation of peptidyl-threonine phosphorylation phosphorylation regulation of protein metabolic process regulation of macromolecule metabolic process macromolecule modification regulation of phosphorus metabolic process regulation of phosphorylation macromolecule metabolic process peptidyl-threonine phosphorylation cellular response to nitrogen compound response to endogenous stimulus response to peptide hormone cellular response to peptide hormone stimulus response to oxygen-containing compound response to nitrogen compound response to glucagon cellular response to oxygen-containing compound cellular response to glucagon stimulus cellular response to endogenous stimulus cellular response to chemical stimulus response to hormone response to chemical cellular response to hormone stimulus response to activity adenylate cyclase-modulating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway regulation of peptidyl-serine phosphorylation peptidyl-serine modification peptidyl-serine phosphorylation positive regulation of peptidyl-serine phosphorylation protein kinase A signaling negative regulation of execution phase of apoptosis regulation of execution phase of apoptosis execution phase of apoptosis behavior multicellular organismal process feeding behavior adenylate cyclase-activating G protein-coupled receptor signaling pathway protein localization regulation of localization establishment of protein localization nitrogen compound transport localization cellular macromolecule localization regulation of biological quality regulation of peptide hormone secretion regulation of hormone levels establishment of protein localization to extracellular region protein secretion establishment of localization regulation of protein secretion regulation of secretion cellular localization regulation of hormone secretion regulation of protein localization regulation of peptide secretion transport hormone secretion protein localization to extracellular region peptide secretion secretion by cell regulation of secretion by cell amide transport signal release secretion regulation of transport regulation of peptide transport regulation of establishment of protein localization cell-cell signaling export from cell regulation of protein transport peptide transport protein transport regulation of cellular localization regulation of insulin secretion peptide hormone secretion macromolecule localization hormone transport insulin secretion positive regulation of establishment of protein localization carbohydrate homeostasis establishment of localization in cell positive regulation of insulin secretion involved in cellular response to glucose stimulus positive regulation of insulin secretion positive regulation of peptide hormone secretion intracellular glucose homeostasis cellular response to carbohydrate stimulus chemical homeostasis response to glucose glucose homeostasis positive regulation of protein localization insulin secretion involved in cellular response to glucose stimulus homeostatic process positive regulation of secretion by cell positive regulation of protein transport positive regulation of hormone secretion response to monosaccharide response to carbohydrate positive regulation of secretion cellular response to hexose stimulus intracellular chemical homeostasis cellular response to monosaccharide stimulus positive regulation of peptide secretion cellular response to glucose stimulus positive regulation of protein secretion response to hexose cellular homeostasis positive regulation of transport regulation of insulin secretion involved in cellular response to glucose stimulus regulation of calcium ion import regulation of calcium ion transport positive regulation of calcium ion transport positive regulation of calcium ion import regulation of monoatomic ion transport calcium ion transport metal ion transport positive regulation of monoatomic ion transport monoatomic ion transport calcium ion import monoatomic cation transport regulation of metal ion transport regulation of catalytic activity regulation of transferase activity positive regulation of molecular function positive regulation of protein kinase activity positive regulation of transferase activity positive regulation of catalytic activity regulation of protein kinase activity regulation of molecular function positive regulation of kinase activity regulation of kinase activity	cell periphery cellular anatomical structure plasma membrane membrane membrane-bounded organelle intracellular anatomical structure membrane-enclosed lumen intracellular membrane-bounded organelle endomembrane system intracellular organelle lumen endoplasmic reticulum lumen intracellular organelle organelle lumen organelle cell periphery cellular anatomical structure plasma membrane membrane membrane-bounded organelle intracellular anatomical structure membrane-enclosed lumen intracellular membrane-bounded organelle endomembrane system intracellular organelle lumen endoplasmic reticulum lumen intracellular organelle organelle lumen organelle endoplasmic reticulum cytoplasm extracellular region vesicle lumen intracellular vesicle cytoplasmic vesicle lumen secretory granule lumen cytoplasmic vesicle secretory granule secretory vesicle vesicle extracellular space

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B	IPR011249	Metalloenzyme, LuxS/M16 peptidase-like	Homologous Superfamily
A, B	IPR050626	Peptidase M16	Family
A, B	IPR032632	Peptidase M16, middle/third domain	Domain
A, B	IPR001431	Peptidase M16, zinc-binding site	Binding Site
A, B	IPR007863	Peptidase M16, C-terminal	Domain
A, B	IPR054734	Coenzyme PQQ synthesis protein F-like, C-terminal lobe, domain 4	Domain
A, B	IPR011765	Peptidase M16, N-terminal	Domain
C, D	IPR000532	Glucagon/GIP/secretin/VIP	Domain
C, D	IPR015550	Glucagon	Family

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B	Pharos: P14735	Alzheimer disease Presenile dementia atopic eczema large cell medulloblastoma malignant ependymoma osteosarcoma psoriasis atypical teratoid rhabdoid tumor glioblastoma lung cancer non-alcoholic fatty liver disease ovarian cancer schizophrenia amyotrophic lateral sclerosis dementia Alzheimer disease Presenile dementia atopic eczema large cell medulloblastoma malignant ependymoma osteosarcoma psoriasis atypical teratoid rhabdoid tumor glioblastoma lung cancer non-alcoholic fatty liver disease ovarian cancer schizophrenia amyotrophic lateral sclerosis dementia invasive ductal breast carcinoma lymphoplasmacytic lymphoma non-small cell lung carcinoma
C, D	Pharos: P01275	obesity disorder hyperglycemia hyperinsulinism type 2 diabetes mellitus malignant colon neoplasm hypertensive disorder Aberrant Crypt Foci colitis congestive heart failure vascular disease heart disease poisoning stomach disease pancreatic intraductal papillary-mucinous neoplasm with low grade dysplasia heart failure obesity disorder hyperglycemia hyperinsulinism type 2 diabetes mellitus malignant colon neoplasm hypertensive disorder Aberrant Crypt Foci colitis congestive heart failure vascular disease heart disease poisoning stomach disease pancreatic intraductal papillary-mucinous neoplasm with low grade dysplasia heart failure prediabetes syndrome hyperlipidemia kidney disease coronary artery disease pancreatic insulinoma pancreatitis hypotensive disorder Crohn disease maturity-onset diabetes of the young non-alcoholic fatty liver disease familial hyperlipidemia pancreatic intraductal papillary-mucinous carcinoma short bowel syndrome hyperinsulinemic hypoglycemia benign colon neoplasm hypoglycemia colonic neoplasm inherited lipid metabolism disorder constipation disorder metabolic acidosis

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.