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Importance of the structure of the RGD‐containing loop in the disintegrins echistatin and eristostatin for recognition of αIIbβ3 and αvβ3 integrins
Author(s) -
McLane Mary Ann,
Vijay-Kumar Senadhi,
Marcinkiewicz Cezary,
Calvete Juan J.,
Niewiarowski Stefan
Publication year - 1996
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(96)00716-8
Subject(s) - disintegrin , vitronectin , integrin , chemistry , stereochemistry , ligand (biochemistry) , biochemistry , receptor , metalloproteinase , enzyme
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: 20 CKRARGDDMDDYC 32 and 23 CRVARGDWNDDYC 35 , respectively. Mapping of eristostatin peptides obtained by proteolytic digestion suggested that it has the same alignment of SS 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.