Viles, John H.;
Mitchell, John B. O.;
Gough, Sharon L.;
Doyle, Paul M.;
Harris, C. John;
Sadler, Peter J.;
Thornton, Janet M.
Multiple Solution Conformations of the Integrin‐Binding Cyclic Pentapeptide Cyclo(‐Ser‐d‐Leu‐Asp‐Val‐Pro‐) : Analysis of the (φ,ψ) Space Available to Cyclic Pentapeptides
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Medientyp:
E-Artikel
Titel:
Multiple Solution Conformations of the Integrin‐Binding Cyclic Pentapeptide Cyclo(‐Ser‐d‐Leu‐Asp‐Val‐Pro‐) : Analysis of the (φ,ψ) Space Available to Cyclic Pentapeptides
:
Analysis of the (φ,ψ) Space Available to Cyclic Pentapeptides
Beteiligte:
Viles, John H.;
Mitchell, John B. O.;
Gough, Sharon L.;
Doyle, Paul M.;
Harris, C. John;
Sadler, Peter J.;
Thornton, Janet M.
Beschreibung:
<jats:p>The aqueous solution structure of the cyclic pentapeptide cyclo(‐Ser‐<jats:sc>d</jats:sc>‐Leu‐Asp‐Val‐Pro‐) has been determined by two‐dimensional <jats:sup>1</jats:sup>H‐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 <jats:italic>cis</jats:italic>‐proline as part of a type‐VIa2 β‐turn encompassing residues Asp‐Val‐<jats:italic>cis</jats:italic>‐Pro‐Ser. The second component (16%) contained only <jats:italic>trans</jats:italic>‐amide bonds, and a type‐VIII, β‐turn formed by residues Val‐Pro‐Ser‐<jats:sc>d</jats:sc>‐Leu. These structures are discussed in relation to the (φ,ψ) 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; α<jats:sub>4</jats:sub>β<jats:sub>1</jats:sub>) 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.</jats:p>