3bef

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spinqualitylabelsall models 3bef, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of thrombin bound to the extracellular fragment of PAR1

Overview

Na(+) binding near the primary specificity pocket of thrombin promotes the, procoagulant, prothrombotic, and signaling functions of the enzyme. The, effect is mediated allosterically by a communication between the Na(+), site and regions involved in substrate recognition. Using a panel of 78, Ala mutants of thrombin, we have mapped the allosteric core of residues, that are energetically linked to Na(+) binding. These residues are, Asp-189, Glu-217, Asp-222, and Tyr-225, all in close proximity to the, bound Na(+). Among these residues, Asp-189 shares with Asp-221 the, important function of transducing Na(+) binding into enhanced catalytic, activity. None of the residues of exosite I, exosite II, or the 60-loop, plays a significant role in Na(+) binding and allosteric transduction., X-ray crystal structures of the Na(+)-free (slow) and Na(+)-bound (fast), forms of thrombin, free or bound to the active site inhibitor, H-d-Phe-Pro-Arg-chloromethyl-ketone, document the conformational changes, induced by Na(+) binding. The slow --> fast transition results in, formation of the Arg-187:Asp-222 ion pair, optimal orientation of Asp-189, and Ser-195 for substrate binding, and a significant shift of the side, chain of Glu-192 linked to a rearrangement of the network of water, molecules that connect the bound Na(+) to Ser-195 in the active site. The, changes in the water network and the allosteric core explain the, thermodynamic signatures linked to Na(+) binding and the mechanism of, thrombin activation by Na(+). The role of the water network uncovered in, this study establishes a new paradigm for the allosteric regulation of, thrombin and other Na(+)-activated enzymes involved in blood coagulation, and the immune response.

About this Structure

3BEF is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Thrombin, with EC number 3.4.21.5 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Molecular dissection of Na+ binding to thrombin., Pineda AO, Carrell CJ, Bush LA, Prasad S, Caccia S, Chen ZW, Mathews FS, Di Cera E, J Biol Chem. 2004 Jul 23;279(30):31842-53. Epub 2004 May 19. PMID:15152000

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