1RTF
COMPLEX OF BENZAMIDINE WITH THE CATALYTIC DOMAIN OF HUMAN TWO CHAIN TISSUE PLASMINOGEN ACTIVATOR [(TC)-T-PA]
Summary for 1RTF
| Entry DOI | 10.2210/pdb1rtf/pdb |
| Descriptor | TWO CHAIN TISSUE PLASMINOGEN ACTIVATOR, PHOSPHATE ION, BENZAMIDINE, ... (5 entities in total) |
| Functional Keywords | serine protease, fibrinolytic enzymes |
| Biological source | Homo sapiens (human) More |
| Cellular location | Secreted, extracellular space: P00750 |
| Total number of polymer chains | 2 |
| Total formula weight | 30494.35 |
| Authors | |
| Primary citation | Lamba, D.,Bauer, M.,Huber, R.,Fischer, S.,Rudolph, R.,Kohnert, U.,Bode, W. The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator J.Mol.Biol., 258:117-135, 1996 Cited by PubMed Abstract: 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. PubMed: 8613982DOI: 10.1006/jmbi.1996.0238 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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