5KSV

Crystal structure of HLA-DQ2.5-CLIP2

Summary for 5KSV

• Entry DOI: 10.2210/pdb5ksv/pdb
• Related: 5KSU
• Descriptor: MHC class II HLA-DQ-alpha chain, MHC class II HLA-DQ-beta-1, HLA class II histocompatibility antigen gamma chain, ... (4 entities in total)
• Functional Keywords: hla-dq2.5, clip2, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 47765.85

Authors

Nguyen, T.B.,Jayaraman, P.,Bergseng, E.,Madhusudhan, M.S.,Kim, C.-Y.,Sollid, L.M. (deposition date: 2016-07-10, release date: 2017-04-05, Last modification date: 2024-10-23)

Primary citation

Nguyen, T.B.,Jayaraman, P.,Bergseng, E.,Madhusudhan, M.S.,Kim, C.Y.,Sollid, L.M.
Unraveling the structural basis for the unusually rich association of human leukocyte antigen DQ2.5 with class-II-associated invariant chain peptides.
J. Biol. Chem., 292:9218-9228, 2017

PubMed Abstract: Human leukocyte antigen (HLA)-DQ2.5 (**) is a class-II major histocompatibility complex protein associated with both type 1 diabetes and celiac disease. One unusual feature of DQ2.5 is its high class-II-associated invariant chain peptide (CLIP) content. Moreover, HLA-DQ2.5 preferentially binds the non-canonical CLIP2 over the canonical CLIP1. To better understand the structural basis of HLA-DQ2.5's unusual CLIP association characteristics, better insight into the HLA-DQ2.5·CLIP complex structures is required. To this end, we determined the X-ray crystal structure of the HLA-DQ2.5· CLIP1 and HLA-DQ2.5·CLIP2 complexes at 2.73 and 2.20 Å, respectively. We found that HLA-DQ2.5 has an unusually large P4 pocket and a positively charged peptide-binding groove that together promote preferential binding of CLIP2 over CLIP1. An α9-α22-α24-α31-β86-β90 hydrogen bond network located at the bottom of the peptide-binding groove, spanning from the P1 to P4 pockets, renders the residues in this region relatively immobile. This hydrogen bond network, along with a deletion mutation at α53, may lead to HLA-DM insensitivity in HLA-DQ2.5. A molecular dynamics simulation experiment reported here and recent biochemical studies by others support this hypothesis. The diminished HLA-DM sensitivity is the likely reason for the CLIP-rich phenotype of HLA-DQ2.5.

PubMed: 28364043
DOI: 10.1074/jbc.M117.785139

Experimental method

X-RAY DIFFRACTION (2.195 Å)