6NPR

Crystal structure of H-2Dd with C84-C139 disulfide in complex with gp120 derived peptide P18-I10


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.37 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.182 

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Literature

Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection.

McShan, A.C.Devlin, C.A.Overall, S.A.Park, J.Toor, J.S.Moschidi, D.Flores-Solis, D.Choi, H.Tripathi, S.Procko, E.Sgourakis, N.G.

(2019) Proc Natl Acad Sci U S A 116: 25602-25613

  • DOI: https://doi.org/10.1073/pnas.1915562116
  • Primary Citation of Related Structures:  
    6NPR

  • PubMed Abstract: 

    The interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance. Here, we demonstrate that the molecular chaperone TAP-binding protein related (TAPBPR) associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized toward the α 2 domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α 2 domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at "hotspot" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the α 1 2 helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of 1) chaperoning unstable MHC-I molecules with broad allele-specificity at early stages of their folding process, and 2) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, toward editing the repertoire of displayed antigens.


  • Organizational Affiliation

    Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
H-2 class I histocompatibility antigen, D-D alpha chain
A, C
276Mus musculusMutation(s): 0 
Gene Names: H2-D1
UniProt
Find proteins for P01900 (Mus musculus)
Explore P01900 
Go to UniProtKB:  P01900
Entity Groups  
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UniProt GroupP01900
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulin
B, D
100Homo sapiensMutation(s): 0 
Gene Names: B2MCDABP0092HDCMA22P
UniProt & NIH Common Fund Data Resources
Find proteins for P61769 (Homo sapiens)
Explore P61769 
Go to UniProtKB:  P61769
PHAROS:  P61769
GTEx:  ENSG00000166710 
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UniProt GroupP61769
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
ARG-GLY-PRO-GLY-ARG-ALA-PHE-VAL-THR-ILEE [auth P],
F [auth R]
10Human immunodeficiency virus 1Mutation(s): 0 
UniProt
Find proteins for P04578 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2))
Explore P04578 
Go to UniProtKB:  P04578
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04578
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.37 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.182 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.99α = 90
b = 105.33β = 90
c = 117.27γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United States1R35GM125034-01
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United States1R01AI143997

Revision History  (Full details and data files)

  • Version 1.0: 2020-01-22
    Type: Initial release
  • Version 1.1: 2023-10-11
    Changes: Data collection, Database references, Refinement description