1rtf

From Proteopedia

Revision as of 14:49, 15 February 2008

COMPLEX OF BENZAMIDINE WITH THE CATALYTIC DOMAIN OF HUMAN TWO CHAIN TISSUE PLASMINOGEN ACTIVATOR [(TC)-T-PA]

Overview

Tissue-type plasminogen activator (t-PA), a multidomainal serine, proteinase of the trypsin-family, catalyses the rate-limiting step in, fibrinolysis, the activation of plasminogen to the fibrin-degrading, proteinase plasmin. Trigonal crystals have been obtained of the, recombinant catalytic domain of human-two-chain t-PA, consisting of a 17, residue A chain and the 252 residue B chain. Its X-ray crystal structure, has been solved applying Patterson and isomorphous replacement methods, and has been crystallographically refined to an R-value of 0.184 at 2.3 A, resolution. The chain fold, active-site geometry and Ile276-Asp477 salt, bridge are similar to that observed for trypsin. A few surface-located, insertion loops differ significantly, however. The disulfide bridge, Cys315-Cys384, practically unique to the plasminogen activators, is, incorporated without drastic conformational changes as the insertion loop, preceding Cys384 makes a bulge on the molecular surface. The unique basic, insertion loop Lys296-Arg304 flanking the primed subsites, which has been, shown to be of importance for PAI-1 binding and for fibrin specificity, is, partially disordered; it can therefore freely adapt to proteins docking to, the active site. The S1 pocket of t-PA is almost identical to that of, trypsin, whereas the S2 site is considerably reduced in size by the, imposing Tyr368 side-chain, in agreement with the measured preference for, P1 Arg and P2 Gly residues. The neighbouring S3-S4 hydrophobic groove is, mainly hydrophobic in nature. The structure of the proteinase domain of, two-chain t-PA suggests that the formation of a salt bridge between Lys429, and Asp477 may contribute to the unusually high catalytic activity of, single-chain t-PA, thus stabilizing the catalytically active conformation, without unmasking the Ile276 amino terminus. Modeling studies show that, the covalently bound kringle 2 domain in full-length t-PA could interact, with an extended hydrophobic groove in the catalytic domain; in such a, docking geometry its "lysine binding site" and the "fibrin binding patch", of the catalytic domain are in close proximity.

Disease

Known disease associated with this structure: Plasminogen activator deficiency OMIM:[173370]

About this Structure

1RTF is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as T-plasminogen activator, with EC number 3.4.21.68 Full crystallographic information is available from OCA.

Reference

The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator., Lamba D, Bauer M, Huber R, Fischer S, Rudolph R, Kohnert U, Bode W, J Mol Biol. 1996 Apr 26;258(1):117-35. PMID:8613982

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