Importance of the structure of the RGD‐containing loop in the disintegrins echistatin and eristostatin for recognition of αIIbβ3 and αvβ3 integrins

FEBS Letters

Vijay-Kumar, Senadhi²  Calvete, Juan J.¹  Marcinkiewicz, Cezary³  Niewiarowski, Stefan³  McLane, Mary Ann³ 

[1] Tierarztlische Hochschule, Hannover-Kirchrode, Germany;Department of Biochemistry and Fels Research Institute, Temple University School of Medicine, Philadelphia, PA 19140 USA;Sol Sherry Center for Thrombosis Research, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140, USA

关键词: RGD loop;    Integrin αIIbβ3;    Integrim αvβ3;    Disintegrin;    Disulfide bridge;    RGD;    argine-glycine-aspartic acid;    HUVEC;    human umbilical vein endothelial cell;    CHO;    Chinese hamster ovary;    NMR;    nuclear magnetic resonance;    PBST;    phosphate buffered saline-Tween;    RMS;    root-mean-square;   

DOI  :  10.1016/0014-5793(96)00716-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Echistatin and eristostatin are structurally homologous disintegrins which exhibit significant functional differences in interaction with various integrins. We hypothesized that this may reflect differences in the sequences of their RGD loops: ²⁰CKRARGDDMDDYC³² and ²³CRVARGDWNDDYC³⁵, respectively. Mapping of eristostatin peptides obtained by proteolytic digestion suggested that it has the same alignment of SS bridges as echistatin. Synthetic echistatin D27W resembled eristostatin since it had increased platelet aggregation inhibitory activity, increased potency to block fibrinogen binding to αIIbβ3, and decreased potency to block vitronectin binding to αvβ3 as compared to wild-type echistatin. Since eristostatin and echistatin have a similar pattern of disulfide bridges, we constructed molecular models of eristostatin based on echistatin NMR coordinates. The RGD loops of eristostatin and echistatin D27W were wider than echistatin's due to the placement of tryptophan (rather than aspartic acid) immediately after the RGD sequence. We propose a hypothesis that the width and shape of the RGD loop are important ligand structural features that affect fitting of ligand to the binding pocket of αIIbβ3 and αvβ3.

【 授权许可】

Unknown