'''REFINED 2.3 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF BOVINE THROMBIN COMPLEXES FORMED WITH THE BENZAMIDINE AND ARGININE-BASED THROMBIN INHIBITORS NAPAP, 4-TAPAP AND MQPA: A STARTING POINT FOR IMPROVING ANTITHROMBOTICS'''
===REFINED 2.3 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF BOVINE THROMBIN COMPLEXES FORMED WITH THE BENZAMIDINE AND ARGININE-BASED THROMBIN INHIBITORS NAPAP, 4-TAPAP AND MQPA: A STARTING POINT FOR IMPROVING ANTITHROMBOTICS===
==Overview==
<!--
Well-diffracting crystals of bovine epsilon-thrombin in complex with several "non-peptidic" benzamidine and arginine-based thrombin inhibitors have been obtained by co-crystallization. The 2.3 A crystal structures of three complexes formed either with NAPAP, 4-TAPAP, or MQPA, were solved by Patterson search methods and refined to crystallographic R-values of 0.167 to 0.178. The active-site environment of thrombin is only slightly affected by binding of the different inhibitors; in particular, the exposed "60-insertion loop" essentially maintains its typical projecting structure. The D-stereoisomer of NAPAP and the L-stereoisomer of MQPA bind to thrombin with very similar conformations, as previously inferred from their binding to bovine trypsin; the arginine side-chain of the latter inserts into the specificity pocket in a "non-canonical" manner. The L-stereoisomer of 4-TAPAP, whose binding geometry towards trypsin was only poorly defined, is bound to the thrombin active-site in a compact conformation. In contrast to NAPAP, the distal p-amidino/guanidino groups of 4-TAPAP and MQPA do not interact with the carboxylate group of Asp189 in the thrombin specificity pocket in a "symmetrical" twin N-twin O manner, but through "lateral" single N-twin O contacts; in contrast to the p-amidino group of 4-TAPAP, however, the guanidyl group of MQPA packs favourably in the pocket due to an elaborate hydrogen bond network, which includes two entrapped water molecules. These thrombin structures confirm previous conclusions of the important role of the intermolecular hydrogen bonds formed with Gly216, and of the good sterical fit of the terminal bulky hydrophobic inhibitor groups with the hydrophobic aryl binding site and the S2-cavity, respectively, for tight thrombin active site binding of these non-peptidic inhibitors. These accurate crystal structures are presumed to be excellent starting points for the design and the elaboration of improved antithrombotics.
The line below this paragraph, {{ABSTRACT_PUBMED_1518046}}, adds the Publication Abstract to the page
(as it appears on PubMed at http://www.pubmed.gov), where 1518046 is the PubMed ID number.
-->
{{ABSTRACT_PUBMED_1518046}}
==About this Structure==
==About this Structure==
Line 24:
Line 28:
[[Category: Bode, W.]]
[[Category: Bode, W.]]
[[Category: Brandstetter, H.]]
[[Category: Brandstetter, H.]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 15:30:34 2008''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 01:58:18 2008''
Revision as of 01:58, 1 July 2008
This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.
REFINED 2.3 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF BOVINE THROMBIN COMPLEXES FORMED WITH THE BENZAMIDINE AND ARGININE-BASED THROMBIN INHIBITORS NAPAP, 4-TAPAP AND MQPA: A STARTING POINT FOR IMPROVING ANTITHROMBOTICSREFINED 2.3 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF BOVINE THROMBIN COMPLEXES FORMED WITH THE BENZAMIDINE AND ARGININE-BASED THROMBIN INHIBITORS NAPAP, 4-TAPAP AND MQPA: A STARTING POINT FOR IMPROVING ANTITHROMBOTICS
1ETR is a Single protein structure. Full crystallographic information is available from OCA.
ReferenceReference
Refined 2.3 A X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics., Brandstetter H, Turk D, Hoeffken HW, Grosse D, Sturzebecher J, Martin PD, Edwards BF, Bode W, J Mol Biol. 1992 Aug 20;226(4):1085-99. PMID:1518046
