4X5X

HLA-DR1 mutant bN82A with covalently linked CLIP106-120(M107W)

Summary for 4X5X

• Entry DOI: 10.2210/pdb4x5x/pdb
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-1 beta chain (2 entities in total)
• Functional Keywords: mhc ii, immune system, self antigen, invariant chain, clip
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01903 P04229
• Total number of polymer chains: 4
• Total formula weight: 96230.23

Authors

Guenther, S.,Freund, C. (deposition date: 2014-12-06, release date: 2016-03-09, Last modification date: 2024-10-16)

Primary citation

Wieczorek, M.,Sticht, J.,Stolzenberg, S.,Gunther, S.,Wehmeyer, C.,El Habre, Z.,Alvaro-Benito, M.,Noe, F.,Freund, C.
MHC class II complexes sample intermediate states along the peptide exchange pathway.
Nat Commun, 7:13224-13224, 2016

PubMed Abstract: The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII's ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual's MHC restricted immune response.

PubMed: 27827392
DOI: 10.1038/ncomms13224

Experimental method

X-RAY DIFFRACTION (3.199 Å)