6LVZ

Crystal structure of TLR7/Cpd-3 (SM-394830) complex

PDB DOI: https://doi.org/10.2210/pdb6LVZ/pdb

Classification: IMMUNE SYSTEM
Organism(s): Macaca mulatta
Expression System: Drosophila melanogaster
Mutation(s): Yes

Deposited: 2020-02-06 Released: 2020-11-11
Deposition Author(s): Zhang, Z., Ohto, U., Shimizu, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.83 Å
R-Value Free: 0.245
R-Value Work: 0.187
R-Value Observed: 0.190

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

Structural analysis reveals TLR7 dynamics underlying antagonism.

Tojo, S., Zhang, Z., Matsui, H., Tahara, M., Ikeguchi, M., Kochi, M., Kamada, M., Shigematsu, H., Tsutsumi, A., Adachi, N., Shibata, T., Yamamoto, M., Kikkawa, M., Senda, T., Isobe, Y., Ohto, U., Shimizu, T.

(2020) Nat Commun 11: 5204-5204

PubMed: 33060576 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/s41467-020-19025-z
Primary Citation of Related Structures:
6LVX, 6LVY, 6LVZ, 6LW0, 6LW1

PubMed Abstract:
Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases.

Organizational Affiliation

Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan. [email protected].

Macromolecule Content

Total Structure Weight: 195.02 kDa
Atom Count: 12,864
Modelled Residue Count: 1,544
Deposited Residue Count: 1,646
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 [auth B], B [auth A]	823	Macaca mulatta	Mutation(s): 10 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: 5	Glycosylation Focus chain A [auth B] Focus chain B [auth A]
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C, D	3		N-Glycosylation	Interactions Focus chain C Focus chain D Interactions & Density Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G15407YE GlyCosmos: G15407YE GlyGen: G15407YE

Entity ID: 3
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	E	2		N-Glycosylation	Interactions Focus chain E Interactions & Density 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
EWX (Subject of Investigation/LOI) Query on EWX Download Ideal Coordinates CCD File SDF format, chain S [auth B] SDF format, chain T [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B]	S [auth B], T [auth B]	6-azanyl-2-(2-methoxyethoxy)-9-(pyridin-3-ylmethyl)-7H-purin-8-one C₁₄ H₁₆ N₆ O₃ XWTNEKDECZWUJX-UHFFFAOYSA-N		Interactions Focus chain S [auth B] Focus chain T [auth B] Interactions & Density Focus chain S [auth B] Focus chain T [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain F [auth B] SDF format, chain H [auth B] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain U [auth A] SDF format, chain V [auth A] SDF format, chain W [auth A] SDF format, chain G [auth B] MOL2 format, chain F [auth B] MOL2 format, chain H [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain U [auth A] MOL2 format, chain V [auth A] MOL2 format, chain W [auth A] MOL2 format, chain G [auth B] mmCIF format, chain F [auth B] mmCIF format, chain H [auth B] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain U [auth A] mmCIF format, chain V [auth A] mmCIF format, chain W [auth A] mmCIF format, chain G [auth B]	F [auth B] G [auth B] H [auth B] I [auth B] J [auth B] F [auth B], G [auth B], H [auth B], I [auth B], J [auth B], K [auth B], L [auth B], M [auth B], U [auth A], V [auth A], W [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain F [auth B] Focus chain G [auth B] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Interactions & Density Focus chain F [auth B] Focus chain G [auth B] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain AA [auth A] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain X [auth A] SDF format, chain Y [auth A] SDF format, chain Z [auth A] SDF format, chain R [auth B] MOL2 format, chain AA [auth A] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain X [auth A] MOL2 format, chain Y [auth A] MOL2 format, chain Z [auth A] MOL2 format, chain R [auth B] mmCIF format, chain AA [auth A] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain X [auth A] mmCIF format, chain Y [auth A] mmCIF format, chain Z [auth A] mmCIF format, chain R [auth B]	AA [auth A] N [auth B] O [auth B] P [auth B] Q [auth B] AA [auth A], N [auth B], O [auth B], P [auth B], Q [auth B], R [auth B], X [auth A], Y [auth A], Z [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain AA [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain X [auth A] Focus chain Y [auth A] Focus chain Z [auth A] Interactions & Density Focus chain AA [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain X [auth A] Focus chain Y [auth A] Focus chain Z [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.83 Å
R-Value Free: 0.245
R-Value Work: 0.187
R-Value Observed: 0.190
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 98.548	α = 90
b = 139.079	β = 90
c = 149.2	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
PDB_EXTRACT	data extraction
XDS	data reduction
Aimless	data scaling
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2020-11-11

Deposition Author(s):

Zhang, Z.

Ohto, U.

Shimizu, T.

Revision History (Full details and data files)

Version 1.0: 2020-11-11
Type: Initial release
Version 1.1: 2023-11-29
Changes: Data collection, Database references, Refinement description
Version 1.2: 2024-10-16
Changes: Structure summary

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Help and Resources

6LVZ

Crystal structure of TLR7/Cpd-3 (SM-394830) complex

Structural analysis reveals TLR7 dynamics underlying antagonism.

Entity ID: 1

UniProt

Entity Groups

Glycosylation

Sequence Annotations

Expand

Entity ID: 2

Glycosylation Resources