On the structure of histidine and its role in enzyme active sites
- Julius Rebek Jr.
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A structural refinement is proposed for the mechanistic details of the action of the serine proteases. The proposal involves ring flipping of the imidazole function of the histidine side chain as a vehicle for proton transfer. The geometric feasibility of this motion is established by molecular graphics analysis of the crystal structure ofα-chymotrypsin. It is suggested that the shape of histidine is as important as its pK a for its function at the active sites of enzymes.
- Vedani, A.; Dunitz, J. D.J. Am. Chem. Soc. 1985,107, 7653; see also Gandour, R. D.; Nabulsi, N. A. R.; Fronczek, F. R.J. Am. Chem. Soc. In press, and references therein. We thank Professor Gandour for a preprint of this manuscript.
- For a review see Venkatasubban, K. S.; Schowen, R. L.Crit. Rev. Biochem. 1984,17, 1.
- Sprang, S.; Standing, T.; Fletterick, R. J.; Stroud, R. M.; Finer-Moore, J.; Xuong, N.-H.; Hamlin, R.; Rutter, W. J.; Craik, C. S.Science (Washington, DC)1987,237, 905; Craik, C. S.; Roczniak, S.; Largman, C.; Rutter, W. J.id, 909; Carter, P.; Wells, J. A.Nature (London),1988,332, 564.
- For alternate interpretations concerning the function of the carboxylate see Warshel, A.; Russel, S.J. Am. Chem. Soc.,1986,108, 6569; Bachovchin, W. W.Biochemistry,1986,25, 7751.
- Gandour, R. D.Bioorg. Chem. 1981,10, 169.
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- MACROMODEL 2.0 (W. C. Still, Columbia University) was used in the analysis of the active site on an Evans & Sutherland PS 390 system.
- For related suggestions involving the bidentate nature of carboxylates see Knowles, J. R.; Albery, W. J.Acc. Chem. Res. 1977,10, 105 and Schepartz, A.; Breslow, R.J. Am. Chem. Soc. 1987,109, 1814.
- An extensive discussion of motions elsewhere in the active sites of serine proteases is available: Gorenstein, D. G.Chem. Rev. 1987,87, 1047.
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- On the structure of histidine and its role in enzyme active sites
Volume 1, Issue 1 , pp 129-131
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- Julius Rebek Jr. (1)
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- 1. Department of Chemistry, University of Pittsburgh, 15260, Pittsburgh, Pennsylvania, USA