8TTZ

Crystal structure of monkey TLR7 ectodomain with compound 20

PDB DOI: https://doi.org/10.2210/pdb8TTZ/pdb

Classification: IMMUNE SYSTEM
Organism(s): Macaca mulatta
Expression System: Drosophila melanogaster
Mutation(s): No

Deposited: 2023-08-15 Released: 2024-02-07
Deposition Author(s): Critton, D.A.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.14 Å
R-Value Free: 0.241
R-Value Work: 0.194
R-Value Observed: 0.196

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.

Poudel, Y.B., He, L., Cox, M., Zhang, Q., Johnson, W.L., Cong, Q., Cheng, H., Chowdari, N.S., Tarby, C., Donnell, A.F., Broekema, M., O'Malley, D.P., Zhang, Y., A M Subbaiah, M., Kumar, B.V., Subramani, L., Wang, B., Li, Y.X., Sivaprakasam, P., Critton, D., Mulligan, D., Sandhu, B., Xie, C., Ramakrishnan, R., Nagar, J., Dudhgaonkar, S., Oderinde, M.S., Murtaza, A., Schieven, G.L., Mathur, A., Gavai, A.V., Vite, G., Gangwar, S.

(2024) ACS Med Chem Lett 15: 181-188

PubMed: 38352830 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.3c00455
Primary Citation of Related Structures:
8TTY, 8TTZ

PubMed Abstract:
We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro , these agonists significantly induced secretion of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

Organizational Affiliation

Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.

Macromolecule Content

Total Structure Weight: 195.71 kDa
Atom Count: 13,003
Modelled Residue Count: 1,544
Deposited Residue Count: 1,634
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Toll-like receptor 7	A, B	817	Macaca mulatta	Mutation(s): 0 Gene Names: TLR7
UniProt
Find proteins for B3Y653 (Macaca mulatta) Explore B3Y653 Go to UniProtKB: B3Y653
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	B3Y653
Glycosylation
Glycosylation Sites: 7	Glycosylation Focus chain A Focus chain B
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C, D, E	2		N-Glycosylation	Interactions Focus chain C Focus chain D Focus chain E Interactions & Density Focus chain C Focus chain D Focus chain E
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
QCX (Subject of Investigation/LOI) Query on QCX Download Ideal Coordinates CCD File SDF format, chain EA [auth A] SDF format, chain GA [auth B] MOL2 format, chain EA [auth A] MOL2 format, chain GA [auth B] mmCIF format, chain EA [auth A] mmCIF format, chain GA [auth B]	EA [auth A], GA [auth B]	(3S)-3-({5-amino-1-[(2-methoxy-4-{[(oxan-4-yl)amino]methyl}phenyl)methyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}amino)hexan-1-ol C₂₅ H₃₇ N₇ O₃ PVTVUOZOPYPPBJ-FQEVSTJZSA-N		Interactions Focus chain EA [auth A] Focus chain GA [auth B] Interactions & Density Focus chain EA [auth A] Focus chain GA [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain HA [auth B] SDF format, chain I [auth A] SDF format, chain JA [auth B] SDF format, chain K [auth A] SDF format, chain KA [auth B] SDF format, chain L [auth A] SDF format, chain LA [auth B] SDF format, chain IA [auth B] SDF format, chain J [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain HA [auth B] MOL2 format, chain I [auth A] MOL2 format, chain JA [auth B] MOL2 format, chain K [auth A] MOL2 format, chain KA [auth B] MOL2 format, chain L [auth A] MOL2 format, chain LA [auth B] MOL2 format, chain IA [auth B] MOL2 format, chain J [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain HA [auth B] mmCIF format, chain I [auth A] mmCIF format, chain JA [auth B] mmCIF format, chain K [auth A] mmCIF format, chain KA [auth B] mmCIF format, chain L [auth A] mmCIF format, chain LA [auth B] mmCIF format, chain IA [auth B] mmCIF format, chain J [auth A]	F [auth A] G [auth A] H [auth A] HA [auth B] I [auth A] F [auth A], G [auth A], H [auth A], HA [auth B], I [auth A], IA [auth B], J [auth A], JA [auth B], K [auth A], KA [auth B], L [auth A], LA [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain HA [auth B] Focus chain I [auth A] Focus chain IA [auth B] Focus chain J [auth A] Focus chain JA [auth B] Focus chain K [auth A] Focus chain KA [auth B] Focus chain L [auth A] Focus chain LA [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain HA [auth B] Focus chain I [auth A] Focus chain IA [auth B] Focus chain J [auth A] Focus chain JA [auth B] Focus chain K [auth A] Focus chain KA [auth B] Focus chain L [auth A] Focus chain LA [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain AA [auth A] SDF format, chain CA [auth A] SDF format, chain DA [auth A] SDF format, chain FA [auth A] SDF format, chain MA [auth B] SDF format, chain NA [auth B] SDF format, chain O [auth A] SDF format, chain OA [auth B] SDF format, chain P [auth A] SDF format, chain Q [auth A] SDF format, chain QA [auth B] SDF format, chain R [auth A] SDF format, chain S [auth A] SDF format, chain SA [auth B] SDF format, chain T [auth A] SDF format, chain U [auth A] SDF format, chain V [auth A] SDF format, chain W [auth A] SDF format, chain X [auth A] SDF format, chain Y [auth A] SDF format, chain BA [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain PA [auth B] SDF format, chain RA [auth B] SDF format, chain TA [auth B] SDF format, chain UA [auth B] SDF format, chain VA [auth B] SDF format, chain Z [auth A] MOL2 format, chain AA [auth A] MOL2 format, chain CA [auth A] MOL2 format, chain DA [auth A] MOL2 format, chain FA [auth A] MOL2 format, chain MA [auth B] MOL2 format, chain NA [auth B] MOL2 format, chain O [auth A] MOL2 format, chain OA [auth B] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain QA [auth B] MOL2 format, chain R [auth A] MOL2 format, chain S [auth A] MOL2 format, chain SA [auth B] MOL2 format, chain T [auth A] MOL2 format, chain U [auth A] MOL2 format, chain V [auth A] MOL2 format, chain W [auth A] MOL2 format, chain X [auth A] MOL2 format, chain Y [auth A] MOL2 format, chain BA [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain PA [auth B] MOL2 format, chain RA [auth B] MOL2 format, chain TA [auth B] MOL2 format, chain UA [auth B] MOL2 format, chain VA [auth B] MOL2 format, chain Z [auth A] mmCIF format, chain AA [auth A] mmCIF format, chain CA [auth A] mmCIF format, chain DA [auth A] mmCIF format, chain FA [auth A] mmCIF format, chain MA [auth B] mmCIF format, chain NA [auth B] mmCIF format, chain O [auth A] mmCIF format, chain OA [auth B] mmCIF format, chain P [auth A] mmCIF format, chain Q [auth A] mmCIF format, chain QA [auth B] mmCIF format, chain R [auth A] mmCIF format, chain S [auth A] mmCIF format, chain SA [auth B] mmCIF format, chain T [auth A] mmCIF format, chain U [auth A] mmCIF format, chain V [auth A] mmCIF format, chain W [auth A] mmCIF format, chain X [auth A] mmCIF format, chain Y [auth A] mmCIF format, chain BA [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain PA [auth B] mmCIF format, chain RA [auth B] mmCIF format, chain TA [auth B] mmCIF format, chain UA [auth B] mmCIF format, chain VA [auth B] mmCIF format, chain Z [auth A]	AA [auth A] BA [auth A] CA [auth A] DA [auth A] FA [auth A] AA [auth A], BA [auth A], CA [auth A], DA [auth A], FA [auth A], M [auth A], MA [auth B], N [auth A], NA [auth B], O [auth A], OA [auth B], P [auth A], PA [auth B], Q [auth A], QA [auth B], R [auth A], RA [auth B], S [auth A], SA [auth B], T [auth A], TA [auth B], U [auth A], UA [auth B], V [auth A], VA [auth B], W [auth A], X [auth A], Y [auth A], Z [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain AA [auth A] Focus chain BA [auth A] Focus chain CA [auth A] Focus chain DA [auth A] Focus chain FA [auth A] Focus chain M [auth A] Focus chain MA [auth B] Focus chain N [auth A] Focus chain NA [auth B] Focus chain O [auth A] Focus chain OA [auth B] Focus chain P [auth A] Focus chain PA [auth B] Focus chain Q [auth A] Focus chain QA [auth B] Focus chain R [auth A] Focus chain RA [auth B] Focus chain S [auth A] Focus chain SA [auth B] Focus chain T [auth A] Focus chain TA [auth B] Focus chain U [auth A] Focus chain UA [auth B] Focus chain V [auth A] Focus chain VA [auth B] Focus chain W [auth A] Focus chain X [auth A] Focus chain Y [auth A] Focus chain Z [auth A] Interactions & Density Focus chain AA [auth A] Focus chain BA [auth A] Focus chain CA [auth A] Focus chain DA [auth A] Focus chain FA [auth A] Focus chain M [auth A] Focus chain MA [auth B] Focus chain N [auth A] Focus chain NA [auth B] Focus chain O [auth A] Focus chain OA [auth B] Focus chain P [auth A] Focus chain PA [auth B] Focus chain Q [auth A] Focus chain QA [auth B] Focus chain R [auth A] Focus chain RA [auth B] Focus chain S [auth A] Focus chain SA [auth B] Focus chain T [auth A] Focus chain TA [auth B] Focus chain U [auth A] Focus chain UA [auth B] Focus chain V [auth A] Focus chain VA [auth B] Focus chain W [auth A] Focus chain X [auth A] Focus chain Y [auth A] Focus chain Z [auth A]