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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 and 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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-[[Image:1epr.jpg|left|200px]]<br /><applet load="1epr" size="450" color="white" frame="true" align="right" spinBox="true"
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 '''A STRUCTURAL COMPARISON OF 21 INHIBITOR COMPLEXES OF THE ASPARTIC PROTEINASE FROM ENDOTHIA PARASITICA'''<br />
 ==Overview==
-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.
+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 Structure==
-EPR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with DPH and TSM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Endothiapepsin Endothiapepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.22 3.4.23.22] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EPR OCA].
+EPR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=DPH:'>DPH</scene> and <scene name='pdbligand=TSM:'>TSM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Endothiapepsin Endothiapepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.22 3.4.23.22] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EPR OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Badasso, M.]]
-[[Category: Blundell, T.L.]]
+[[Category: Blundell, T L.]]
-[[Category: Cooper, J.B.]]
+[[Category: Cooper, J B.]]
 [[Category: Crawford, M.]]
 [[Category: DPH]]
@@ Line 21: / Line 21: @@
 [[Category: hydrolase(acid proteinase)]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 14:12:44 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:30:17 2008''