1epr
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A STRUCTURAL COMPARISON OF 21 INHIBITOR COMPLEXES OF THE ASPARTIC PROTEINASE FROM ENDOTHIA PARASITICA
OverviewOverview
The aspartic proteinases are an important family of enzymes associated, with several pathological conditions such as hypertension (renin), gastric, ulcers (pepsin), neoplastic disease (cathepsins D and E), and AIDS (HIV, proteinase). Studies of inhibitor binding are therefore of great, importance for design of novel inhibitors for potential therapeutic, applications. Numerous X-ray analyses have shown that transition-state, isostere inhibitors of aspartic proteinases bind in similar extended, conformations in the active-site cleft of the target enzyme. Upon, comparison of 21 endothiapepsin inhibitor complexes, the hydrogen bond, lengths were found to be shortest where the isostere (P1-P'1) interacts, with the enzyme's catalytic aspartate pair. Hydrogen bonds with good, geometry also occur at P'2, and more so at P3, where a conserved water, molecule is involved in the interactions. Weaker interactions also occur, at P2, where the side-chain conformations of the inhibitors appear to be, more variable than at the more tightly held positions. At P2 and, to a, lesser extent, P3, the side-chain conformations depend intriguingly on, interactions with spatially adjacent side chains, namely P'1 and P1, respectively. The tight binding at P1-P'1, P3, and P'2 is also reflected, in the larger number of van der Waals contacts and the large decreases in, solvent-accessible area at these positions, as well as their low, temperature factors. Our analysis substantiates earlier proposals for the, locations of protons in the transition-state complex. Aspartate 32 is, probably ionized in the complexes, its charge being stabilized by 1, or, sometimes 2, hydrogen bonds from the transition-state analogues at P1. The, detailed comparison also indicates that the P1 and P2 residues of, substrate in the ES complex may be strained by the extensive binding, interactions at P3, P'1, and P'2 in a manner that would facilitate, hydrolysis of the scissile peptide bond.
About this StructureAbout this Structure
1EPR is a Single protein structure of sequence from [1] with DPH and TSM as ligands. Active as Endothiapepsin, with EC number 3.4.23.22 Full crystallographic information is available from OCA.
ReferenceReference
A structural comparison of 21 inhibitor complexes of the aspartic proteinase from Endothia parasitica., Bailey D, Cooper JB, Protein Sci. 1994 Nov;3(11):2129-43. PMID:7703859
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