Role of a Buried Acid Group in the Mechanism of Action of Chymotrypsin

Blow, D. M.; Birktoft, Jens J.; Hartley, Brian

doi:10.1038/221337a0

Cited by 1,081 publications

(556 citation statements)

References 19 publications

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“…Acylation of serine-195 is accompanied by disruption of the "charge relay system" [3]. One may therefore assume that this system plays an important role in maintaining the native conformation of the active site.…”

Section: Introductionmentioning

confidence: 99%

Effect of methylation of the histidine residue in the active site of α‐chymotrypsin on the conformational stability of the enzyme

Antonov

Vorotyntseva

1972

FEBS Letters

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Section: Introductionmentioning

confidence: 99%

Effect of methylation of the histidine residue in the active site of α‐chymotrypsin on the conformational stability of the enzyme

Antonov

Vorotyntseva

1972

FEBS Letters

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“…Another role of water, which is important for thrombin and trypsin, is the structural stabilization of cavities (Rashin et al, 1986;Meyer, 1992;Williams et al, 1994). Water can also play an important role in protein catalysis, as in hydrolysis by serine proteases (Blow et al, 1969;Perona et al, Reprint requests to: Leslie A. Kuhn Singer et al, 1993); proteins stripped of their primary hydration layer are observed to lose catalytic function (Rupley & Careri,199 1 ).…”

mentioning

confidence: 99%

Cluster analysis of consensus water sites in thrombin and trypsin shows conservation between serine proteases and contributions to ligand specificity

Sanschagrin

Kuhn

1998

Protein Science

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Cluster analysis is presented as a technique for analyzing the conservation and chemistry of water sites from independent protein structures, and applied to thrombin, trypsin, and bovine pancreatic trypsin inhibitor (BPTI) to locate shared water sites, as well as those contributing to specificity. When several protein structures are superimposed, complete linkage cluster analysis provides an objective technique for resolving the continuum of overlaps between water sites into a set of maximally dense microclusters of overlapping water molecules, and also avoids reliance on any one structure as a reference. Water sites were clustered for ten superimposed thrombin structures. three trypsin structures, and four BPTI structures. For thrombin, 19% of the 708 microclusters, representing unique water sites, contained water molecules from at least half of the structures, and 4% contained waters from all 10. For trypsin, 77% of the 106 microclusters contained water sites from at least half of the structures, and 57% contained waters from all three. Water site conservation correlated with several environmental features: highly conserved microclusters generally had more protein atom neighbors, were in a more hydrophilic environment, made more hydrogen bonds to the protein, and were less mobile. There were significant overlaps between thrombin and trypsin conserved water sites, which did not localize to their similar active sites, but were concentrated in buried regions including the solvent channel surrounding the Na' site in thrombin, which is associated with ligand selectivity. Cluster analysis also identified water sites conserved in thrombin but not trypsin, and vice versa, providing a list of water sites that may contribute to ligand discrimination. Thus, in addition to facilitating the analysis of water sites from multiple structures, cluster analysis provides a useful tool for distinguishing between conserved features within a protein family and those conferring specificity.

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“…The equilibrium between the inactive and active conformations of chymotrypsin has been studied as a function of pH [3] and these results are sufficient to describe the events necessary for activity. The pH dependence indicates that the "charge relay system" [9] has the same ionisation state in both conformations; the only major ionisation seen between pH 3 and 13 is that of Ile-16 [3]. (If the pK, of Asp 102 altered significantly during the conformational change then this would cause a large perturbation in the equilibrium constant).…”

Section: Resultsmentioning

confidence: 99%

The catalytic activity of the inactive conformation of δ‐chymotrypsin

Fersht

1973

FEBS Letters

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Role of a Buried Acid Group in the Mechanism of Action of Chymotrypsin

Cited by 1,081 publications

References 19 publications

Effect of methylation of the histidine residue in the active site of α‐chymotrypsin on the conformational stability of the enzyme

Effect of methylation of the histidine residue in the active site of α‐chymotrypsin on the conformational stability of the enzyme

Cluster analysis of consensus water sites in thrombin and trypsin shows conservation between serine proteases and contributions to ligand specificity

The catalytic activity of the inactive conformation of δ‐chymotrypsin

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