1gwb

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==Overview==
==Overview==
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Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in, mediating the arrest of platelets at sites of vascular damage. GPIb binds, to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a, thrombus. To investigate the molecular basis of GPIb regulation and ligand, binding, we have determined the structure of the N-terminal domain of the, GPIb(alpha) chain (residues 1-279). This structure is the first determined, from the cell adhesion/signaling class of leucine-rich repeat (LRR), proteins and reveals the topology of the characteristic disulfide-bonded, flanking regions. The fold consists of an N-terminal beta-hairpin, eight, leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic, region. The structure also demonstrates a novel LRR motif in the form of, an M-shaped arrangement of three tandem beta-turns. Negatively charged, binding surfaces on the LRR concave face and anionic region indicate, two-step binding kinetics to vWF-A1, which can be regulated by an, unmasking mechanism involving conformational change of a key loop. Using, molecular docking of the GPIb and vWF-A1 crystal structures, we were also, able to model the GPIb.vWF-A1 complex.
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Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.
==Disease==
==Disease==
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[[Category: von willebrand disease]]
[[Category: von willebrand disease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:54:40 2008''

Revision as of 10:54, 21 February 2008

Image:1gwb.gif

1gwb, resolution 2.8Å

Drag the structure with the mouse to rotate

STRUCTURE OF GLYCOPROTEIN 1B

Contents

Overview

Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.

Disease

Known diseases associated with this structure: Bernard-Soulier syndrome, type A OMIM:[606672], Nonarteritic anterior ischemic optic neuropathy, susceptibility to OMIM:[606672], von Willebrand disease, platelet-type OMIM:[606672]

About this Structure

1GWB is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation., Uff S, Clemetson JM, Harrison T, Clemetson KJ, Emsley J, J Biol Chem. 2002 Sep 20;277(38):35657-63. Epub 2002 Jun 26. PMID:12087105

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