Esters of iodinated tyrosine as inhibitors of chymotrypsin

Garratt, Clifford J.; Harrison, D. M.

doi:10.1016/0014-5793(70)80480-x

Cited by 5 publications

(1 citation statement)

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“…An excellent discussion and summary of these data is presented by Bosshard and Berger (1974). To summarize their discussion, they conclude that the hydrophobic Si site of chymotrypsin is rigidly defined and that the binding of many large virtual substrates although of high binding energy (e.g., /Modo-TV-acetyltyrosine ethyl ester (Garratt and Harrison, 1970) and O-methyl-A-acetyltyrosine methyl ester (Kunda et al, 1972)) "may lead to some distortion or misfit in the substrate-enzyme interactions at the catalytic locus which, partially or completely, abolishes catalysis." Since the «-octyl side chain of octyl isocyanate is longer than the iodotyrosine side chain, approximately as long as a methyl ether derivative, yet binds in a productive (inhibitory) manner to the active site of chymotrypsin; the data presented here define a deeper pocket than previously observed (Steitz et al, 1969).…”

Section: Discussionmentioning

confidence: 99%

Alkyl isocyanates as active site-specific reagents for serine proteases. Location of alkyl binding site in chymotrypsin by x-ray diffraction

Brown¹

1975

Biochemistry

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The structure of octylcarbamoyl-alpha-chymotrypsin to a resolution of 3.0 A is described. The n-octyl side chain of the active site directed irreversible inactivator octyl isocyanate is bound exclusively in the hydrophobic substrate binding pocket. The n-octyl isocyanate forms a planar urethane bond with the Ser-195 Ogamma and extends approximately 1 A deeper into the hydrophobic pocket than the indolyl group of indoleacryloyl-alpha-chymotrypsin (Henderson, R. (1970), J. Mol. Biol. 54, 341). All the structural changes are essentially identical with those observed in indoleacryloyl-alpha-chymotrypsin including the observation of a hydrogen bonded water molecule between the carbonyl oxygen of the octylcarbamoyl group and the imidazole group of His-57. The observed mode of n-octyl alkyl binding to chymotrypsin is consistent with the hypothesis proposed earlier (Brown, W. E. and Wold, F. (1973), Biochemistry 12, 828).

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Section: Discussionmentioning

confidence: 99%

Alkyl isocyanates as active site-specific reagents for serine proteases. Location of alkyl binding site in chymotrypsin by x-ray diffraction

Brown¹

1975

Biochemistry

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Theories of enzyme specificity and their application to proteases and aminoacyl-Transfer RNA synthetases

Bosshard

1976

Experientia

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The question of enzyme specificity which is a corollary of the phenomenon of biological recognition is reviewed. The following theories are outlined briefly: non-productive binding, induced fit, transition state binding, the general strain theory and the kinetic proofreading hypothesis. Data on proteolytic enzymes and aminoacyl-tRNA synthetases are discussed in the light of predictions made by the various theories. The specificity of inhibitor and substrate binding to chymotrypsin and subtilisins is revealed at the sub-molecular level as an example of binding specificity. Kinetic specificity is experimentally distinguished from binding specificity. Conformational adaptability of enzyme and substrate, which is crucial in some theories, is documented by data on aminoacyl-tRNA synthetases. Expected and observed specificity of tRNA charging is discussed with regard to a theoretical limit of specificity. Additional means seem necessary beside those contained in the isolated enzyme-substrate system to account for the high specificity of most synthetases. In conclusion, we have arrived at quite good explanations for moderate specificity such as is displayed by many proteases, but there are still ample difficulties in the understanding of highly specific enzyme reactions.

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