A single residue exchange between two HLA-B27 alleles triggers increased peptide flexibility.
For more than 30 years, human leukocyte antigen B27 (HLA-B27) has been known to be closely related to the autoimmune disease ankylosing spondylitis, yet little is known about the molecular mechanisms of pathogenesis. Crystal structures of two closely related, but differently disease-associated, subtypes (B*2705 and B*2709) also did not resolve this situation as they revealed the bound nonapeptide in essentially identical conformations. As the peptide is part of putative binding epitopes for the T cell receptor, we performed molecular dynamics simulations to gain deeper insight into the dynamic behaviour of HLA-B27 molecules. We find increased flexibility of the peptide in the binding groove of subtype B*2709 due to weaker interactions in the F pocket. Possible implications of this flexibility for T cell recognition and signalling are discussed.
Starikov
Ewgeni B
EB
Department of Biosciences at NOVUM, Karolinska Institutet, 141 57 Huddinge, Sweden.
Starikow
Ewgeni B
EB
Nilsson
Lennart
L
Hülsmeyer
Martin
M
D000483:Alleles; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D015796:HLA-B27 Antigen / Q000737:chemistry*; D006860:Hydrogen Bonding; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D009038:Motion; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000596:Amino Acids; D015796:HLA-B27 Antigen; D010455:Peptides