4K5Y

Crystal structure of human corticotropin-releasing factor receptor 1 (CRF1R) in complex with the antagonist CP-376395

PDB DOI: https://doi.org/10.2210/pdb4K5Y/pdb

Classification: MEMBRANE PROTEIN, RECEPTOR
Organism(s): Homo sapiens, Tequatrovirus T4
Expression System: Trichoplusia ni
Mutation(s): Yes
Membrane Protein: Yes OPMPDBTMMemProtMDmpstruc

Deposited: 2013-04-15 Released: 2013-07-17
Deposition Author(s): Hollenstein, K., Kean, J., Bortolato, A., Cheng, R.K.Y., Dore, A.S., Jazayeri, A., Cooke, R.M., Weir, M., Marshall, F.H.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.98 Å
R-Value Free: 0.265
R-Value Work: 0.242
R-Value Observed: 0.243

Starting Models: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Structure of class B GPCR corticotropin-releasing factor receptor 1.

Hollenstein, K., Kean, J., Bortolato, A., Cheng, R.K., Dore, A.S., Jazayeri, A., Cooke, R.M., Weir, M., Marshall, F.H.

(2013) Nature 499: 438-443

PubMed: 23863939 Search on PubMed
DOI: https://doi.org/10.1038/nature12357
Primary Citation of Related Structures:
4K5Y

PubMed Abstract:
Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.

Organizational Affiliation

Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.

Macromolecule Content

Total Structure Weight: 156.77 kDa
Atom Count: 8,823
Modelled Residue Count: 1,051
Deposited Residue Count: 1,323
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Corticotropin-releasing factor receptor 1, T4-Lysozyme chimeric construct	A, B, C	441	Homo sapiens, Tequatrovirus T4	Mutation(s): 16 Gene Names: CRF1R, CRFR, CRFR1, CRHR, CRHR1, E EC: 3.2.1.17 Membrane Entity: Yes
UniProt & NIH Common Fund Data Resources
Find proteins for P00720 (Enterobacteria phage T4) Explore P00720 Go to UniProtKB: P00720
Find proteins for P34998 (Homo sapiens) Explore P34998 Go to UniProtKB: P34998
PHAROS: P34998 GTEx: ENSG00000120088
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Groups	P00720P34998
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
PGW Query on PGW Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B]	K [auth B], L [auth B], M [auth B]	(1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate C₄₀ H₇₇ O₁₀ P PAZGBAOHGQRCBP-HGWHEPCSSA-N		Interactions Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B]
OLC Query on OLC Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain J [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain J [auth B]	F [auth A], G [auth A], J [auth B]	(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate C₂₁ H₄₀ O₄ RZRNAYUHWVFMIP-GDCKJWNLSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B]
1Q5 Query on 1Q5 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain I [auth B] SDF format, chain R [auth C] MOL2 format, chain D [auth A] MOL2 format, chain I [auth B] MOL2 format, chain R [auth C] mmCIF format, chain D [auth A] mmCIF format, chain I [auth B] mmCIF format, chain R [auth C]	D [auth A], I [auth B], R [auth C]	3,6-dimethyl-N-(pentan-3-yl)-2-(2,4,6-trimethylphenoxy)pyridin-4-amine C₂₁ H₃₀ N₂ O VIZBSVDBNLAVAW-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain I [auth B] Focus chain R [auth C] Interactions & Density Focus chain D [auth A] Focus chain I [auth B] Focus chain R [auth C]
OLA Query on OLA Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain S [auth C] MOL2 format, chain E [auth A] MOL2 format, chain S [auth C] mmCIF format, chain E [auth A] mmCIF format, chain S [auth C]	E [auth A], S [auth C]	OLEIC ACID C₁₈ H₃₄ O₂ ZQPPMHVWECSIRJ-KTKRTIGZSA-N		Interactions Focus chain E [auth A] Focus chain S [auth C] Interactions & Density Focus chain E [auth A] Focus chain S [auth C]
1PE Query on 1PE Download Ideal Coordinates CCD File SDF format, chain N [auth B] MOL2 format, chain N [auth B] mmCIF format, chain N [auth B]	N [auth B]	PENTAETHYLENE GLYCOL C₁₀ H₂₂ O₆ JLFNLZLINWHATN-UHFFFAOYSA-N		Interactions Focus chain N [auth B] Interactions & Density Focus chain N [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] MOL2 format, chain H [auth A] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] mmCIF format, chain H [auth A] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B]	H [auth A], O [auth B], P [auth B], Q [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain H [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Interactions & Density Focus chain H [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
1Q5	PDBBind: 4K5Y	Kd: 6.7 (nM) from 1 assay(s)
1Q5	BindingDB: 4K5Y	IC50: 5.1 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.98 Å
R-Value Free: 0.265
R-Value Work: 0.242
R-Value Observed: 0.243
Space Group: P 2 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 86.559	α = 90
b = 123.968	β = 90
c = 166.834	γ = 90

Software Package:

Software Name	Purpose
GDA	data collection
PHASER	phasing
PHENIX	refinement
XDS	data reduction
Aimless	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-07-17

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2013-07-17
Type: Initial release
Version 1.1: 2013-10-23
Changes: Database references
Version 1.2: 2017-08-09
Changes: Refinement description, Source and taxonomy
Version 1.3: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description
Version 1.4: 2024-11-20
Changes: Structure summary

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Help and Resources

4K5Y

Crystal structure of human corticotropin-releasing factor receptor 1 (CRF1R) in complex with the antagonist CP-376395

Structure of class B GPCR corticotropin-releasing factor receptor 1.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)