J. W. Fenton II, F. Ni, J. I. Witting (auth.), Goran's The Design of Synthetic Inhibitors of Thrombin PDF

By J. W. Fenton II, F. Ni, J. I. Witting (auth.), Goran Claeson, Michael F. Scully, Vijay V. Kakkar, John Deadman (eds.)

ISBN-10: 1489924183

ISBN-13: 9781489924186

ISBN-10: 1489924205

ISBN-13: 9781489924209

In one iteration, the various components interested by blood coagulation became actual protein entities, remoted in natural shape, expressed by way of recombinant DNA ideas, and subjected to constitution elucidation by way of the modem equipment of actual chemistry, viz. , X-ray diffraction, and NMR, ESR and fluorescence spectroscopy. the foremost milestone during this box used to be the leap forward accomplished through W. Bode, R. Huber and their colleagues in 1989 in of human a-thrombin, inhibited with D-Phe-Pro-Arg choosing the crystal constitution chioromethyl ketone. the provision of this constitution will vastly facilitate the translation of experiments designed to realize an figuring out of the interatomic interactions among this enzyme and fibrinogen and its different substrates. whilst, it offers a rational foundation for the layout and synthesis of inhibitors of thrombin, the topic of this symposium. The symposium was once equipped in 4 classes: (1) Structural beneficial properties of the interplay of thrombin with substrates and inhibitors, (2) artificial inhibitors, (3) Hirudin and its analogues, and (4) Pharmacological and scientific issues. This booklet comprises summaries of lots of the papers awarded, and takes its rigbful position between others that offer a finished photograph of our present wisdom approximately thrombin, viz. the 1977 quantity entitled "Chemistry and Biology of Thrombin", edited by way of R. L. Lundblad, J. W. Fenton II, and ok. G. Mann, and the 1992 quantity entitled "Thrombin: constitution and Function", edited by means of L. J. Berliner.

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Additional info for The Design of Synthetic Inhibitors of Thrombin

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The catalytic residues His57, Aspl02 and Ser195 of thrombin are labelled together with Aspl89 which is found at the bottom of the primary specificity (SI) pocket. B. Modelled structure of the Arg2' mutant. The arginyl side chain in position 2 can be modelled to make an electrostatic interaction with Aspl89 in the primary specificity pocket. Substitution of Pr060' by alanine or glycine results in a decrease in binding energy (aGb) of about 6 kJ mol-I. Pro60' has 7 contacts closer than 4 A to Tyr76 of thrombin.

This result is consistent with the crystal structure in which the hydroxyl of Tyr63' does not make any hydrogen bonds8 • Tyrosine is necessary in position 63 of the native protein because its hydroxyl group is enzymatically sulphated in the leech and this post-translational modification causes the lO-fold lower Kd value observed with natural hirudin9,3s,4s. The complex of thrombin with a sulphated C-terminal fragment of hirudin indicates that the tyrosine-sulphate is involved in a network of charged hydrogen bonds26.

Hofsteenge, Identification of regions of a-thrombin involved in its interaction with hirudin, Biochemistry 26:4617 (1987). 19. R. Stone, S. Dennis, and J. Hofsteenge, Quantitative evaluation of the contribution of ionic interactions to the formation of the thrombinhirudin complex, Biochemistry 28:6857 (1989). 20. P. A. Parry, J. R. Stone, Intrinsic fluorescence changes and rapid kinetics of the reaction of thrombin with hirudin, 1. BioI. Chem. 267: 15375 (1992). 21. S. Dennis, A. Wallace, J. R.

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The Design of Synthetic Inhibitors of Thrombin by J. W. Fenton II, F. Ni, J. I. Witting (auth.), Goran Claeson, Michael F. Scully, Vijay V. Kakkar, John Deadman (eds.)


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