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PDBsum entry 1epr
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Hydrolase/hydrolase inhibitor
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PDB id
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1epr
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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A structural comparison of 21 inhibitor complexes of the aspartic proteinase from endothia parasitica.
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Authors
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D.Bailey,
J.B.Cooper.
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Ref.
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Protein Sci, 1994,
3,
2129-2143.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 3.
Fig. 3. hydrogen bondinteractions with inhibitorsare shown (top) with agraph showing te donor-acceptor dis-
tances for the 21 nhibitor complexes (+ indicates an 0. . .H-N interaction, @ indicates an 0. . .H-N nteraction with an
at theproton greater than 160'. and X indicates n 0. . .H-0 interaction). Some of theiteractions with the aspartate carbox-
yls willbe van er Waals contactsratherthan hydrogen bonds (see text for discussion of proton locations).
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Figure 5.
Fig. 5. A: distribution of x, angles observed for each position of the inhibitors. The distribution of x2 angles.
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The above figures are
reprinted
by permission from the Protein Society:
Protein Sci
(1994,
3,
2129-2143)
copyright 1994.
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Secondary reference #1
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Title
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The 3d structure at 2 angstroms resolution of endothiapepsin
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Authors
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T.L.Blundell,
J.Jenkins,
B.T.Sewell,
L.H.Pearl,
J.B.Cooper,
I.J.Tickle,
B.Veerapandian,
S.P.Wood.
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Ref.
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j mol biol, 1990,
211,
919.
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