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Well-diffracting cyrstals of bovine ɛ-thrombin in complex with several “non-peptidic” benzamidine and arginine-based thrombin inhibitors have been obtained by co-crystallization. The 2·3Åcrystal 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 …