6KVA

Structure of anti-hCXCR2 abN48-2 in complex with its CXCR2 epitope


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Selection of a picomolar antibody that targets CXCR2-mediated neutrophil activation and alleviates EAE symptoms.

Shi, X.Wan, Y.Wang, N.Xiang, J.Wang, T.Yang, X.Wang, J.Dong, X.Dong, L.Yan, L.Li, Y.Liu, L.Hou, S.Zhong, Z.Wilson, I.A.Yang, B.Yang, G.Lerner, R.A.

(2021) Nat Commun 12: 2547-2547

  • DOI: https://doi.org/10.1038/s41467-021-22810-z
  • Primary Citation of Related Structures:  
    6KVA, 6KVF

  • PubMed Abstract: 

    Receptors and their ligands are important therapeutic targets for about one third of marketed drugs. Here, we describe an epitope-guided approach for selection of antibodies that modulate cellular signaling of targeted receptors. We chose CXC chemokine receptor 2 (CXCR2) in the G-protein coupled receptor superfamily as receptor and a CXCR2 N-terminal peptide for antibody selection. We obtain a highly selective, tight-binding antibody from a 10 11 -member antibody library using combinatorial enrichment. Structural and Hydrogen-Deuterium-Exchange mass spectrometry analyses demonstrate antibody interaction with an N-terminal region of CXCR2 that is part of the IL-8 epitope. The antibody strongly inhibits IL-8-induced and CXCR2-mediated neutrophil chemotaxis in vitro and alleviates hCXCR2-dependent experimental autoimmune encephalomyelitis symptoms in mice. As inappropriate neutrophil migration accompanies many diseases including inflammatory bowel disease, glomerulonephritis, allergic asthma, chronic obstructive pulmonary disease, and cancer, this antibody has potential for development as a therapeutic agent, akin to anti-TNF antibodies. However, an important difference here is that the antibody targets the chemokine receptor and competes with natural ligand, rather than targeting the ligand itself.


  • Organizational Affiliation

    Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
heavy chainA [auth H],
C [auth h]
227Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
light chainB [auth L],
D [auth l]
222Homo sapiensMutation(s): 0 
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Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Peptide from C-X-C chemokine receptor type 2E [auth B],
F [auth b]
11Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P25025 (Homo sapiens)
Explore P25025 
Go to UniProtKB:  P25025
PHAROS:  P25025
GTEx:  ENSG00000180871 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25025
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.685α = 90
b = 96.337β = 109.86
c = 70.783γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of ChinaChina31600619

Revision History  (Full details and data files)

  • Version 1.0: 2020-09-09
    Type: Initial release
  • Version 1.1: 2021-09-22
    Changes: Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Refinement description