5T1A

Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.81 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.235 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.

Zheng, Y.Qin, L.Zacarias, N.V.de Vries, H.Han, G.W.Gustavsson, M.Dabros, M.Zhao, C.Cherney, R.J.Carter, P.Stamos, D.Abagyan, R.Cherezov, V.Stevens, R.C.IJzerman, A.P.Heitman, L.H.Tebben, A.Kufareva, I.Handel, T.M.

(2016) Nature 540: 458-461

  • DOI: https://doi.org/10.1038/nature20605
  • Primary Citation of Related Structures:  
    5T1A

  • PubMed Abstract: 

    CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.


  • Organizational Affiliation

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Chimera protein of CC chemokine receptor type 2 isoform B and T4-lysozyme,Lysozyme508Homo sapiensTequatrovirus T4
This entity is chimeric
Mutation(s): 23 
Gene Names: CCR2CMKBR2eT4Tp126
EC: 3.2.1.17
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P41597 (Homo sapiens)
Explore P41597 
Go to UniProtKB:  P41597
PHAROS:  P41597
GTEx:  ENSG00000121807 
Find proteins for P00720 (Enterobacteria phage T4)
Explore P00720 
Go to UniProtKB:  P00720
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00720P41597
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
73R
Query on 73R

Download Ideal Coordinates CCD File 
B [auth A](3S)-1-{(1S,2R,4R)-4-[methyl(propan-2-yl)amino]-2-propylcyclohexyl}-3-{[6-(trifluoromethyl)quinazolin-4-yl]amino}pyrrolidin-2-one
C26 H36 F3 N5 O
NUJWKQSEJDYCDB-GNRVTEMESA-N
OLC
Query on OLC

Download Ideal Coordinates CCD File 
H [auth A](2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
VT5
Query on VT5

Download Ideal Coordinates CCD File 
C [auth A](2~{R})-1-(4-chloranyl-2-fluoranyl-phenyl)-2-cyclohexyl-3-ethanoyl-4-oxidanyl-2~{H}-pyrrol-5-one
C18 H19 Cl F N O3
VQNLJXWZGVRLBA-MRXNPFEDSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
G [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN

Download Ideal Coordinates CCD File 
I [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
YCM
Query on YCM
A
L-PEPTIDE LINKINGC5 H10 N2 O3 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
73R BindingDB:  5T1A IC50: min: 0.24, max: 4.7 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.81 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.235 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.23α = 90
b = 64.69β = 90
c = 169.98γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR21AI122211

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-14
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Structure summary
  • Version 1.2: 2016-12-28
    Changes: Structure summary
  • Version 1.3: 2017-01-04
    Changes: Database references
  • Version 1.4: 2017-09-13
    Changes: Author supporting evidence
  • Version 1.5: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.6: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description