Protein Engineering vol. 8 no. 8 pp. 823-827, 1995
© 1995 Oxford University Press
RESEARCH-ARTICLE |
Common molecular scaffold for two unrelated RGD molecules
StructuraJ Biology Program, Cancer Research Center, La Jolla Cancer Research Foundation La Jolla, CA 92037 2Department of Vascular Biology and Department of Molecular and Experimental Medicine Scripps Research Institute, La Jolla, CA 92037, USA
1To whom correspondence should be addressed
The sequence arginine-glycine-aspartic acid (RGD) is important for recognition of cell adhesion proteins by cell surface receptors (integrins). This tripeptide sequence is present in a number of proteins including fibronectin, vitronectin, von Willebrand factor and fibrinogen. Specific and selective binding of the RGD sequence by different receptors suggests that the conformational orientation of the tripeptide is critical for stereochemical recognition. The crystal structures of two proteins that contain the RGD signal were determined: (i) the cell-binding type III module of fibronectin (FNm,0) and (ii) an anti-receptor antibody fragment (OPG2) that is a functional RGD ligand mimic with an RYD recognition site in the variable (VH) domain. Both of these modules are folded into ß-barrels with two layers of antiparaJlel ß-sheets enclosing a hydrophobiccore. Since these molecules each contain the RGD (RYD) sequence, there is a unique opportunity for direct structural comparison. The comparison has defined a common molecular scaffold in these two unrelated molecules. Within this framework, the RGD (RYD) sites are located in structurally related loops in the two modules, i.e. at one end of the scaffold in a long loop connecting the last two strands in one of the pVsheets. This shared scaffold is used for the stereochemical presentation of the RGD site for receptor recognition.
Keywords: anti-receptor antibody/cell adhesion/fibronectin/integrin/RGD ligand
Received March 21, 1995; accepted May 19, 1995.