Closed headpiece of integrin αIIbβ3 and its complex with an αIIbβ3-specific antagonist that does not induce opening. Blood 2010 Dec 02;116(23):5050-9
Date
08/04/2010Pubmed ID
20679525Pubmed Central ID
PMC3012599DOI
10.1182/blood-2010-04-281154Scopus ID
2-s2.0-78649747986 (requires institutional sign-in at Scopus site) 101 CitationsAbstract
The platelet integrin α(IIb)β(3) is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the α(IIb)β(3) headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the α(IIb)β(3) headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the α(IIb) subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, α(IIb) Y190 and α(IIb) D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce α(IIb)β(3) to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.
Author List
Zhu J, Zhu J, Negri A, Provasi D, Filizola M, Coller BS, Springer TAAuthor
Jieqing Zhu PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBinding Sites
Fibrinogen
Humans
Mutagenesis, Site-Directed
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Binding
Protein Conformation
X-Ray Diffraction
