4OV5

Structure of HLA-DR1 with a bound peptide with non-optimal alanine in the P1 pocket

Summary for 4OV5

• Entry DOI: 10.2210/pdb4ov5/pdb
• Related: 1AQD
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-1 beta chain, HLA class I histocompatibility antigen, A-2 alpha chain, ... (4 entities in total)
• Functional Keywords: ig-like domain, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01903 P04229; Membrane; Single-pass type I membrane protein: P01892
• Total number of polymer chains: 18
• Total formula weight: 269192.27

Authors

Trenh, P.,Yin, L.,Stern, L.J. (deposition date: 2014-02-20, release date: 2014-07-16, Last modification date: 2024-11-06)

Primary citation

Yin, L.,Trenh, P.,Guce, A.,Wieczorek, M.,Lange, S.,Sticht, J.,Jiang, W.,Bylsma, M.,Mellins, E.D.,Freund, C.,Stern, L.J.
Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide.
J.Biol.Chem., 289:23449-23464, 2014

PubMed Abstract: HLA-DM mediates the exchange of peptides loaded onto MHCII molecules during antigen presentation by a mechanism that remains unclear and controversial. Here, we investigated the sequence and structural determinants of HLA-DM interaction. Peptides interacting nonoptimally in the P1 pocket exhibited low MHCII binding affinity and kinetic instability and were highly susceptible to HLA-DM-mediated peptide exchange. These changes were accompanied by conformational alterations detected by surface plasmon resonance, SDS resistance assay, antibody binding assay, gel filtration, dynamic light scattering, small angle x-ray scattering, and NMR spectroscopy. Surprisingly, all of those changes could be reversed by substitution of the P9 pocket anchor residue. Moreover, MHCII mutations outside the P1 pocket and the HLA-DM interaction site increased HLA-DM susceptibility. These results indicate that a dynamic MHCII conformational determinant rather than P1 pocket occupancy is the key factor determining susceptibility to HLA-DM-mediated peptide exchange and provide a molecular mechanism for HLA-DM to efficiently target unstable MHCII-peptide complexes for editing and exchange those for more stable ones.

PubMed: 25002586
DOI: 10.1074/jbc.M114.585539

Experimental method

X-RAY DIFFRACTION (2.199 Å)