title: Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes.
abstract: Class II major histocompatibility complex (MHC) proteins are involved in initiation of immune responses to foreign antigens via presentation of peptides to receptors of CD4(+) T-cells. An analogous presentation of self-peptides may lead to autoimmune diseases, such as rheumatoid arthritis (RA). The glycopeptide fragment CII259-273, derived from type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of collagen induced arthritis (CIA), a validated model for RA. We have introduced hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273. Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified glycopeptides, although static models predicted similar binding modes as the native type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the hydroxyethylene isosteres disturbed the entire hydrogen bond network between the glycopeptides and A(q). As a consequence the hydroxyethylene isosteric glycopeptides were prone to dissociation from A(q) and unfolding of the β1-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.
authors.affiliation: Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden. anna.linusson@umu.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindgren
authors.forename: Ida E
authors.initials: IE
authors.lastname: Andersson
authors.forename: Lotta
authors.initials: L
authors.lastname: Berg
authors.forename: Doreen
authors.initials: D
authors.lastname: Dobritzsch
authors.forename: Changrong
authors.initials: C
authors.lastname: Ge
authors.forename: Sabrina
authors.initials: S
authors.lastname: Haag
authors.forename: Urszula
authors.initials: U
authors.lastname: Uciechowska
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
mesh_terms: D024043:Collagen Type II / Q000737:chemistry*; D005030:Ethylenes / Q000737:chemistry*; D006020:Glycopeptides / Q000737:chemistry*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D024043:Collagen Type II; D005030:Ethylenes; D006020:Glycopeptides; D000949:Histocompatibility Antigens Class II; C067254:hydroxyethylene