Allosteric Modulation of Primary Specificity of Serine Proteinases

Abstract

The selectivity of serine proteinases action is mediated by high-specifice binding of the proper parts of the protein substrate. Among such protein targets a special place belongs to the areas of functionally conditioned interaction with the active center of the enzyme. Their sharp difference in enzyme affinity is due to synchronous interaction of the binding and allosteric sites of the active site with specific amino acid residues of the substrate that are adequate in specificity and placed in the proper conformation. This paper is devoted to the consideration of the manifestation of allosteric erosion of primary specificity of serine proteinases. Examples of such effects as well as the possibilities of their application are discussed.

Serpins’ Reactive Sites Loops Mobility and Its Functional Value

“…It effectively blocks trypsin, IIa, IXa, XIa, XIIa, activated protein C, neutrophil elastase and chymotrypsin [41].This inhibitor contains methionine (M 358 ↓S 359 I 360 ) in the P 1 -position of the reactive center, which is not typical for either substrates or inhibitors of trypsin-like proteinases. At the same time, the mobility of the reactive center is quite limited, since the P 3 ' and P 4 ' positions are occupied by prolines [31,42].It is likely that when in the "canonical conformation" insertion into the allosteric site of a ligand of the appropriate specificity leads to the "eroding" of the P 1 -specificity of the enzyme and the formation of the primary complex [43].…”

Allosteric Regulation of the Blood Clotting Cascade

“…It is likely that this mobility provides a broad inhibitory specificity of the α1-inhibitor of proteinases in relation to blood clotting factors (Table 2). Placement of the methionine residue in the P1-position of this inhibitor, which is atypical for trypsinlike proteinases, does not become an obstacle for effective enzyme-inhibitor interaction due to the "blurring" of the ligand specificity of the S1-site when the allosteric site S2' is included in the process [24]. The data on the composition of the sites of inactivation cleavage of factors by activated protein C are also of interest (Table 3).…”