title: HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution.
abstract: Human leukocyte antigen (HLA) class I molecules consist of a heavy chain, beta(2)-microglobulin, and a peptide that are noncovalently bound. Certain HLA-B27 subtypes are associated with ankylosing spondylitis (such as HLA-B*2705), whereas others (such as HLA-B*2709) are not. Both differ in only one residue (Asp116 and His116, respectively) in the F pocket that accommodates the peptide C-terminus. An isotope-edited IR spectroscopy study of these HLA-B27 subtypes complexed with the self-peptide RRKWRRWHL was carried out, revealing that the heavy chain is more flexible in the HLA-B*2705 than in the HLA-B*2709 subtype. In agreement with these experimental data, molecular dynamics simulations showed an increased flexibility of the HLA-B*2705 binding groove in comparison with that of the HLA-B*2709 subtype. This difference correlates with an opening of the HLA-B*2705 binding groove, accompanied by a partial detachment of the C-terminal peptide anchor. These combined results demonstrate how the deeply embedded polymorphic heavy-chain residue 116 influences the flexibility of the peptide binding groove in a subtype-dependent manner, a feature that could also influence the recognition of the HLA-B27 complexes by effector cells.
authors.affiliation: Robert Koch-Institut, P 25, Nordufer 20, D-13353 Berlin, Germany. fabianh@rki.de
authors.forename: Heinz
authors.initials: H
authors.lastname: Fabian
authors.forename: Hans
authors.initials: H
authors.lastname: Huser
authors.forename: Daniele
authors.initials: D
authors.lastname: Narzi
authors.forename: Rolf
authors.initials: R
authors.lastname: Misselwitz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Loll
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Rainer A
authors.initials: RA
authors.lastname: Böckmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.forename: Dieter
authors.initials: D
authors.lastname: Naumann
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000737:chemistry / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013167:Spondylitis, Ankylosing / Q000378:metabolism*; D013816:Thermodynamics; D001613:beta 2-Microglobulin / Q000737:chemistry
chemical_list: D015796:HLA-B27 Antigen; D010446:Peptide Fragments; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; D001613:beta 2-Microglobulin