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Proteins. 1998 Sep 1;32(4):459-74.

Variability of the canonical loop conformations in serine proteinases inhibitors and other proteins.

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Institute of Biochemistry and Molecular Biology, University of Wrocław, Poland.


Canonical loops of protein inhibitors of serine proteinases occur in proteins having completely different folds. In this article, conformations of the loops have been analyzed for inhibitors belonging to 10 structurally different families. Using deviation in Calpha-Calpha distances as a criterion for loop similarity, we found that the P3-P3' segment defines most properly the length of the loop. When conformational differences among loops of individual inhibitors were compared using root mean square deviation (rmsd) in atomic coordinates for all main chain atoms (deltar method) and rmsd operating in main chain torsion angles (deltat method), differences of up to 2.1 A and 72.3 degrees, respectively, were observed. Such large values indicate significant conformational differences among individual loops. Nevertheless, the overall geometry of the inhibitor-proteinase interaction is very well preserved, as judged from the similarity of Calpha-Calpha distances between Calpha of catalytic Ser and Calpha of P3-P3' residues in various enzyme-inhibitor complexes. The mode of interaction is very well preserved both in the chymotrypsin and subtilisin families, as distances calculated for subtilisin-inhibitor complexes are almost always within the range of those for chymotrypsin-inhibitor complexes. Complex formation leads to conformational changes of up to 160 degrees for chi1 angle. Side chains of residue P1 and P2' adopt in different complexes a similar orientation (chi1 angle = -60 degrees and -180 degrees, respectively). To check whether the canonical conformation can be found among non-proteinase-inhibitor Brookhaven Protein Data Bank structures, two selection criteria--the allowed main chain dihedral angles and Calpha-Calpha distances for the P3-P3' segment--were applied to all these structures. This procedure detected 132 unique hexapeptide segments in 121 structurally and functionally unrelated proteins. Partial preferences for certain amino acids occurring at particular positions in these hexapeptides could be noted. Further restriction of this set to hexapeptides with a highly exposed P1 residue side chain resulted in 40 segments. The possibility of complexes formation between these segments and serine proteinases was ruled out in molecular modeling due to steric clashes. Several structural features that determine the canonical conformation of the loop both in inhibitors and in other proteins can be distinguished. They include main chain hydrogen bonds both within the P3-P3' segment and with the scaffold region, P3-P4 and P3'-P4' hydrophobic interactions, and finally either hydrophobic or polar interactions involving the P1' residue.

[Indexed for MEDLINE]

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