1aix
From Proteopedia
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HUMAN ALPHA-THROMBIN TERNARY COMPLEX WITH EXOSITE INHIBITOR HIRUGEN AND ACTIVE SITE INHIBITOR PHCH2OCO-D-DPA-PRO-BOROVAL
Contents |
Overview
Thrombin is a multifunctional serine proteinase that plays a key role in, coagulation while exhibiting several other key cellular bioregulatory, functions. The X-ray crystal structure of human alpha-thrombin was, determined in its complex with the specific thrombin inhibitor, D-Phe-Pro-Arg chloromethylketone (PPACK) using Patterson search methods, and a search model derived from trypsinlike proteinases of known spatial, structure (Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R., &, Hofsteenge, J., 1989, EMBO J. 8, 3467-3475). The crystallographic, refinement of the PPACK-thrombin model has now been completed at an R, value of 0.156 (8 to 1.92 A); in particular, the amino- and the, carboxy-termini of the thrombin A-chain are now defined and all side-chain, atoms localized; only proline 37 was found to be in a cis-peptidyl, conformation. The thrombin B-chain exhibits the characteristic polypeptide, fold of trypsinlike serine proteinases; 195 residues occupy topologically, equivalent positions with residues in bovine trypsin and 190 with those in, bovine chymotrypsin with a root-mean-square (r.m.s.) deviation of 0.8 A, for their alpha-carbon atoms. Most of the inserted residues constitute, novel surface loops. A chymotrypsinogen numbering is suggested for, thrombin based on the topological equivalences. The thrombin A-chain is, arranged in a boomeranglike shape against the B-chain globule opposite to, the active site; it resembles somewhat the propeptide of, chymotrypsin(ogen) and is similarly not involved in substrate and, inhibitor binding. Thrombin possesses an exceptionally large proportion of, charged residues. The negatively and positively charged residues are not, distributed uniformly over the whole molecule, but are clustered to form a, sandwichlike electrostatic potential; in particular, two extended patches, of mainly positively charged residues occur close to the carboxy-terminal, B-chain helix (forming the presumed heparin-binding site) and on the, surface of loop segment 70-80 (the fibrin[ogen] secondary binding, exosite), respectively; the negatively charged residues are more clustered, in the ringlike region between both poles, particularly around the active, site. Several of the charged residues are involved in salt bridges; most, are on the surface, but 10 charged protein groups form completely buried, salt bridges and clusters. These electrostatic interactions play a, particularly important role in the intrachain stabilization of the, A-chain, in the coherence between the A- and the B-chain, and in the, surface structure of the fibrin(ogen) secondary binding exosite (loop, segment 67-80).(ABSTRACT TRUNCATED AT 400 WORDS)
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1AIX is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with T19 as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
Reference
The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships., Bode W, Turk D, Karshikov A, Protein Sci. 1992 Apr;1(4):426-71. PMID:1304349
Page seeded by OCA on Mon Nov 12 15:58:58 2007
