1etr
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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
OverviewOverview
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.
About this StructureAbout this Structure
1ETR is a Single protein structure of sequence from [1] with MQI as ligand. Active as Thrombin, with EC number 3.4.21.5 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
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