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'''Crystal Structure of the Complex of the Wild-type Von Willebrand Factor A1 domain and Glycoprotein Ib alpha at 2.6 Angstrom Resolution''' | '''Crystal Structure of the Complex of the Wild-type Von Willebrand Factor A1 domain and Glycoprotein Ib alpha at 2.6 Angstrom Resolution''' | ||
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[[Category: Stahl, M L.]] | [[Category: Stahl, M L.]] | ||
[[Category: Sullivan, F.]] | [[Category: Sullivan, F.]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 09:00:03 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 09:00, 3 May 2008
Crystal Structure of the Complex of the Wild-type Von Willebrand Factor A1 domain and Glycoprotein Ib alpha at 2.6 Angstrom Resolution
OverviewOverview
The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibalpha (GpIbalpha) and the A1 domain of the von Willebrand factor (VWF). Here we report the 2.6-A crystal structure of a complex comprised of the extracellular domain of GpIbalpha and the wild-type A1 domain of VWF. A direct comparison of this structure to a GpIbalpha-A1 complex containing "gain-of-function" mutations, A1-R543Q and GpIbalpha-M239V, reveals specific structural differences between these complexes at sites near the two GpIbalpha-A1 binding interfaces. At the smaller interface, differences in interaction show that the alpha1-beta2 loop of A1 serves as a conformational switch, alternating between an open alpha1-beta2 isomer that allows faster dissociation of GpIbalpha-A1, as observed in the wild-type complex, and an extended isomer that favors tight association as seen in the complex containing A1 with a type 2B von Willebrand Disease (VWD) mutation associated with spontaneous binding to GpIbalpha. At the larger interface, differences in interaction associated with the GpIbalpha-M239V platelet-type VWD mutation are minor and localized but feature discrete gamma-turn conformers at the loop end of the beta-hairpin structure. The beta-hairpin, stabilized by a strong classic gamma-turn as seen in the mutant complex, relates to the increased affinity of A1 binding, and the beta-hairpin with a weak inverse gamma-turn observed in the wild-type complex corresponds to the lower affinity state of GpIbalpha. These findings provide important details that add to our understanding of how both type 2B and platelet-type VWD mutations affect GpIbalpha-A1 binding affinity.
DiseaseDisease
Known disease associated with this structure: Bernard-Soulier syndrome, type A OMIM:[606672], von Willebrand disease, platelet-type OMIM:[606672], Nonarteritic anterior ischemic optic neuropathy, susceptibility to OMIM:[606672]
About this StructureAbout this Structure
1SQ0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations., Dumas JJ, Kumar R, McDonagh T, Sullivan F, Stahl ML, Somers WS, Mosyak L, J Biol Chem. 2004 May 28;279(22):23327-34. Epub 2004 Mar 23. PMID:15039442 Page seeded by OCA on Sat May 3 09:00:03 2008