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PDBsum entry 3b23
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Hydrolase/hydrolase inhibitor
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PDB id
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3b23
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of thrombin-variegin complex: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors
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Structure:
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Thrombin light chain. Chain: a. Synonym: alpha-thrombin, light chain. Engineered: yes. Thrombin heavy chain. Chain: b. Synonym: alpha-thrombin, heavy chain. Engineered: yes. Variegin.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f2. Expressed in: mus musculus. Expression_system_taxid: 10090. Expression_system_cell_line: sp2/0 ag14 mouse myeloma cells (atcc crl-1581). Synthetic: yes.
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Resolution:
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2.40Å
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R-factor:
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0.210
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R-free:
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0.259
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Authors:
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C.Y.Koh,S.Kumar,K.Swaminathan,R.M.Kini
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Key ref:
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C.Y.Koh
et al.
(2011).
Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors.
Plos One,
6,
e26367.
PubMed id:
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Date:
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20-Jul-11
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Release date:
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23-Nov-11
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PROCHECK
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Headers
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References
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P00734
(THRB_HUMAN) -
Prothrombin from Homo sapiens
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Seq:
Struc:
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622 a.a.
29 a.a.
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Enzyme class:
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Chains A, B:
E.C.3.4.21.5
- thrombin.
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Reaction:
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Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
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Plos One
6:e26367
(2011)
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PubMed id:
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Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors.
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C.Y.Koh,
S.Kumar,
M.Kazimirova,
P.A.Nuttall,
U.P.Radhakrishnan,
S.Kim,
P.Jagadeeswaran,
T.Imamura,
J.Mizuguchi,
S.Iwanaga,
K.Swaminathan,
R.M.Kini.
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ABSTRACT
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The inhibition of thrombin is one of the important treatments of pathological
blood clot formation. Variegin, isolated from the tropical bont tick, is a novel
molecule exhibiting a unique 'two-modes' inhibitory property on thrombin active
site (competitive before cleavage, noncompetitive after cleavage). For the
better understanding of its function, we have determined the crystal structure
of the human α-thrombin:synthetic-variegin complex at 2.4 Å resolution. The
structure reveals a new mechanism of thrombin inhibition by disrupting the
charge relay system. Based on the structure, we have designed 17 variegin
variants, differing in potency, kinetics and mechanism of inhibition. The most
active variant is about 70 times more potent than the FDA-approved peptidic
thrombin inhibitor, hirulog-1/bivalirudin. In vivo antithrombotic effects of the
variegin variants correlate well with their in vitro affinities for thrombin.
Our results encourage that variegin and the variants show strong potential for
the development of tunable anticoagulants.
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Links
