6MVL

Crystal structure of VISTA bound to a pH-selective antibody Fab fragment


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.61 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

VISTA is an acidic pH-selective ligand for PSGL-1.

Johnston, R.J.Su, L.J.Pinckney, J.Critton, D.Boyer, E.Krishnakumar, A.Corbett, M.Rankin, A.L.Dibella, R.Campbell, L.Martin, G.H.Lemar, H.Cayton, T.Huang, R.Y.Deng, X.Nayeem, A.Chen, H.Ergel, B.Rizzo, J.M.Yamniuk, A.P.Dutta, S.Ngo, J.Shorts, A.O.Ramakrishnan, R.Kozhich, A.Holloway, J.Fang, H.Wang, Y.K.Yang, Z.Thiam, K.Rakestraw, G.Rajpal, A.Sheppard, P.Quigley, M.Bahjat, K.S.Korman, A.J.

(2019) Nature 574: 565-570

  • DOI: https://doi.org/10.1038/s41586-019-1674-5
  • Primary Citation of Related Structures:  
    6MVL

  • PubMed Abstract: 

    Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer 1,2 . Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies 3 . However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.


  • Organizational Affiliation

    Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. robert.johnston@bms.com.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
V-type immunoglobulin domain-containing suppressor of T-cell activation169Homo sapiensMutation(s): 3 
Gene Names: VSIRC10orf54SISP1VISTAPP2135UNQ730/PRO1412
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H7M9 (Homo sapiens)
Explore Q9H7M9 
Go to UniProtKB:  Q9H7M9
PHAROS:  Q9H7M9
GTEx:  ENSG00000107738 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H7M9
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Antibody Fab fragment heavy chainB [auth H]229Homo sapiensMutation(s): 0 
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Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Antibody Fab fragment light chainC [auth L]215Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
D [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth H]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth H],
J [auth H],
K [auth H],
L [auth H],
M [auth H],
N [auth H],
O [auth L],
P [auth L],
Q [auth L],
R [auth L]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.61 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 
  • Space Group: I 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.166α = 90
b = 125.856β = 90
c = 192.04γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-10-23
    Type: Initial release
  • Version 1.1: 2019-11-06
    Changes: Data collection, Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary