Evidence for a tetrahedral intermediate complex during serpin-proteinase interactions

Matheson, Nancy; Halbeek, Herman van; Travis, James

doi:10.1016/s0021-9258(18)92722-5

Cited by 113 publications

(33 citation statements)

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“…Determination of the target proteinase-induced site of peptidebond cleavage in the RSL of serpins is usually used to diagnose the P1 site of the inhibitor. It is not known when cleavage of the bonds takes place but, by analogy with other serpins, it is likely that peptide-bond scission is a result of denaturing conditions, and that the bond is intact in the native complex (Travis and Salvesen, 1983;Longstaff and Gaffney, 1991;Mast et al, 1991b;Matheson et al, 1991;Bode and Huber, 1992). Chymotrypsin caused two cleavages in the a2-AP RSL, at site 1 and at site 2.…”

Section: Discussionmentioning

confidence: 99%

An examination of the inhibitory mechanism of serpins by analysing the interaction of trypsin and chymotrypsin with α2-antiplasmin

Enghild

Valnickova

Thøgersen

et al. 1993

Biochemical Journal

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Human alpha 2-antiplasmin (alpha 2-AP) has previously been shown to possess overlapping inhibitory sites for trypsin and chymotrypsin [Potempa, Shieh and Travis (1988) Science 241, 699-700]. Since this is currently unique among active-site-directed inhibitors of proteinases, and difficult to explain in terms of accepted inhibitory mechanisms, we re-examined the claim. Initial characterization of purified alpha 2-AP revealed an additional 12 residues preceding the published N-terminus, prompting us to revise the previous numbering. We found that trypsin caused cleavage of the Arg376-Met377 bond in the reactive-site loop of the inhibitor, whereas chymotrypsin caused cleavage at two sites in approx. equal amounts at 37 degrees C: Met374-Ser375 (site 1) and Met377-Ser378 (site 2). At 0 degrees C alpha 2-AP became a more efficient inhibitor of chymotrypsin, and the proportion of cleavage at site 1 declined, indicating that chymotrypsin prefers to react with site 2 at 0 degrees C. Inhibitors of the alpha 2-AP type are inactivated when cleaved in their reactive-site loops by proteinases that they do not inhibit, so we conclude that site 1 is treated as a substrate by chymotrypsin. Site 2 is the inhibitory site for chymotrypsin. We confirm that alpha 2-AP does indeed have overlapping reactive sites for trypsin and chymotrypsin, and since the locations of chymotrypsin-interaction sites vary with temperature, we suggest that alpha 2-AP cannot have rigid reactive-site geometry. More likely, it has a mobile reactive-site loop of the type that has been recently demonstrated for eglin C.

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Section: Discussionmentioning

confidence: 99%

An examination of the inhibitory mechanism of serpins by analysing the interaction of trypsin and chymotrypsin with α2-antiplasmin

Enghild

Valnickova

Thøgersen

et al. 1993

Biochemical Journal

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“…A typical example in this respect is constituted by serine proteases (SP's) enzyme family [3,4,5,6,7,8,9,10,11,12,13]. SP's use the catalytic triad (Ser-195-His-57-Asp-102) to catalyze the hydrolysis of peptides (Fig.…”

Section: Introductionmentioning

confidence: 99%

Serine proteases: An ab initio molecular dynamics study

Santis

Carloni

1999

Proteins

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“…The exceptions to this rule are plasma inhibitors  1 -antitrypsin and  2 -antiplasmin. They are belonging to the serpine family, whose complexes with anhydro-enzymes are unstable [39,40], while they bind covalently to active enzymes [41]. Unlike most protein inhibitors, the reactive centers of serpines are mobile, passing through a "canonical conformation" [42].…”

Section: Fig 2 Spatial Model Of the Complex Of Soybean Trypsin Inhibi...mentioning

confidence: 99%

Allosteric Site of Serine Proteinases: Localization, Functional Role and Manifestations in Vitro

Verevka

2022

GoS

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The study of molecular mechanisms of regulation of biologically active molecules is a necessary condition for understanding the course of the processes mediated by them. Serine proteinases are a large group of enzymes that play a leading role in the regulation of numerous physiological and pathogenic processes. Like many enzymes, SP are allosteric ones. In addition to the active center, they contain the region, whose interaction with corresponding compound changes the activity of enzyme. Various compounds can act as allosteric effectors. They may be substrates, substrate-like compounds, and mimics of some fragments of substrates. Taking into account the importance of serine proteases’ functions, it’s deserve attention the systematic data on localization, functional role and manifestations of allosteric region.

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Evidence for a tetrahedral intermediate complex during serpin-proteinase interactions

Cited by 113 publications

References 0 publications

An examination of the inhibitory mechanism of serpins by analysing the interaction of trypsin and chymotrypsin with α2-antiplasmin

An examination of the inhibitory mechanism of serpins by analysing the interaction of trypsin and chymotrypsin with α2-antiplasmin

Serine proteases: An ab initio molecular dynamics study

Allosteric Site of Serine Proteinases: Localization, Functional Role and Manifestations in Vitro

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