title: Multiple solution conformations of the integrin-binding cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-). Analysis of the (phi, psi) space available to cyclic pentapeptides.
abstract: The aqueous solution structure of the cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-) has been determined by two-dimensional 1H-NMR spectroscopy, combined with a conformational search and distance-geometry calculations. As many as five conformers in slow exchange were observed, and the rate of interconversion between components was measured from the build-up rates of exchange peaks. NMR data allowed the structures of the two predominant conformers to be determined. The major component (66%) contained a cis-proline as part of a type-VIa2 beta-turn encompassing residues Asp-Val-cis-Pro-Ser. The second component (16%) contained only trans-amide bonds, and a type-VIII beta-turn formed by residues Val-Pro-Ser-D-Leu. These structures are discussed in relation to the (phi, psi), space available to the cyclic pentapeptide, determined by a conformational search, and in relation to previously published cyclic-pentapeptide structures. The molecule exhibits activity in a scintillation-proximity assay for the inhibition of the interaction between the integrin very-late antigen-4 (VLA-4; alpha 4 beta 1) and vascular-cell-adhesion molecule-1 (VCAM-1). The structure/activity relationship of the LDV sequence is discussed and related to the recently published X-ray structure of VCAM-1. The relevance of the work to the design of anti-inflammatory drugs is discussed.
authors.affiliation: Department of Chemistry, Birkbeck College, University of London, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Viles
authors.forename: J B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: S L
authors.initials: SL
authors.lastname: Gough
authors.forename: P M
authors.initials: PM
authors.lastname: Doyle
authors.forename: C J
authors.initials: CJ
authors.lastname: Harris
authors.forename: P J
authors.initials: PJ
authors.lastname: Sadler
authors.forename: J M
authors.initials: JM
authors.lastname: Thornton
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D007074:Immunoglobulin G; D007202:Indicators and Reagents; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012996:Solutions; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D007202:Indicators and Reagents; D016023:Integrins; D010456:Peptides, Cyclic; D011993:Recombinant Fusion Proteins; D012996:Solutions; D019010:Vascular Cell Adhesion Molecule-1; C103186:cyclo(seryl-leucyl-aspartyl-valyl-prolyl)