Publication Date:
2003-07-12
Description:
Thrombin bound to platelets contributes to stop bleeding and, in pathological conditions, may cause vascular thrombosis. We have determined the structure of platelet glycoprotein Ibalpha (GpIbalpha) bound to thrombin at 2.3 angstrom resolution and defined two sites in GpIbalpha that bind to exosite II and exosite I of two distinct alpha-thrombin molecules, respectively. GpIbalpha occupancy may be sequential, as the site binding to alpha-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. These interactions may modulate alpha-thrombin function by mediating GpIbalpha clustering and cleavage of protease-activated receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Celikel, Reha -- McClintock, Richard A -- Roberts, James R -- Mendolicchio, G Loredana -- Ware, Jerry -- Varughese, Kottayil I -- Ruggeri, Zaverio M -- HL-31950/HL/NHLBI NIH HHS/ -- HL-42846/HL/NHLBI NIH HHS/ -- HL-48728/HL/NHLBI NIH HHS/ -- HL-55375/HL/NHLBI NIH HHS/ -- R01 HL042846/HL/NHLBI NIH HHS/ -- RR0833/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2003 Jul 11;301(5630):218-21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Thrombosis and Hemostasis, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12855810" target="_blank"〉PubMed〈/a〉
Keywords:
Binding Sites
;
Blood Coagulation
;
Blood Platelets/chemistry/metabolism
;
Crystallization
;
Crystallography, X-Ray
;
Fibrinogen/metabolism
;
Humans
;
Hydrogen Bonding
;
Ligands
;
Models, Molecular
;
Mutation
;
Platelet Aggregation
;
Platelet Glycoprotein GPIb-IX Complex/*chemistry/genetics/*metabolism
;
Protein Binding
;
Protein Conformation
;
Protein Structure, Tertiary
;
Recombinant Proteins/chemistry/metabolism
;
Thrombin/*chemistry/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
