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PDBsum entry 2er7
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Hydrolase/hydrolase inhibitor
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PDB id
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2er7
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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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X-Ray analyses of aspartic proteinases. Iii three-Dimensional structure of endothiapepsin complexed with a transition-State isostere inhibitor of renin at 1.6 a resolution.
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Authors
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B.Veerapandian,
J.B.Cooper,
A.Sali,
T.L.Blundell.
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Ref.
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J Mol Biol, 1990,
216,
1017-1029.
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PubMed id
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Abstract
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The aspartic proteinase, endothiapepsin (EC 3.4.23.6), was complexed with a
highly potent renin inhibitor, H-261 (t-Boc-His-Pro-Phe-His-LeuOHVal-Ile-His),
where OH denotes a hydroxyethylene (-(S) CHOH-CH2-) transition-state isostere in
the scissile bond surrogate. Crystals were grown in a form that has the same
space group P2(1) as the uncomplexed enzyme, but with a 10 A decrease in the
length of the alpha-axis and a 13 degrees decrease in the beta-angle. X-ray data
have been collected to a resolution of 1.6 A. The rotation and translation
parameters defining the position of the enzyme in the unit cell were determined
previously using another enzyme-inhibitor complex that crystallized
isomorphously with that of H-261. The molecule was refined using restrained
least-squares refinement and the positions of non-hydrogen atoms of the
inhibitor and water molecules were defined by difference Fourier techniques. The
enzyme-inhibitor complex and 322 water molecules were further refined to a
crystallographic R-factor of 0.14. Apart from a small rigid group rotation of a
domain comprising residues 190 to 302 and small movements in the flap, there is
little difference in conformation between the complexed and uncomplexed forms of
the enzyme. The inhibitor is bound in an extended conformation along the active
site cleft, and the hydroxyl group of the hydroxyethylene moiety is
hydrogen-bonded to both catalytic aspartate carboxylates. The complex is
stabilized by hydrogen bonds between the main-chain of the inhibitor and the
enzyme. All side-chains of the inhibitor are in van der Waals' contact with
groups in the enzyme and define a series of specificity pockets along the active
site cleft. The study provides useful clues as to how this potent renin
inhibitor (IC50 value of 0.7 x 10(-9) M) may bind renin. In particular it
defines the interactions of the hydroxyethylene transition-state isostere with
the enzyme more precisely than has been previously possible and therefore
provides a useful insight into interactions in the transition state complex.
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Secondary reference #1
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Title
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The active site of aspartic proteinases.
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Authors
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L.Pearl,
T.Blundell.
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Ref.
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Febs Lett, 1984,
174,
96.
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PubMed id
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Secondary reference #2
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Title
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Active site of acid proteinases
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Authors
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T.L.Blundell,
H.B.Jones,
G.Khan,
G.Taylor,
T.S.Sewell,
L.H.Pearl,
S.P.Wood.
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Ref.
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proc febs meet, 1979,
60,
281.
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Secondary reference #3
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Title
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The three-Dimensional structure of acid proteinases
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Authors
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T.L.Blundell,
J.A.Jenkins,
G.Khan,
P.Roy Chowdhury,
T.Sewell,
I.J.Tickle,
E.A.Wood.
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Ref.
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proc febs meet, 1979,
52,
81.
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Secondary reference #4
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Title
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Four-Fold structural repeat in the acid proteases.
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Authors
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T.L.Blundell,
B.T.Sewell,
A.D.Mclachlan.
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Ref.
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Biochim Biophys Acta, 1979,
580,
24-31.
[DOI no: ]
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PubMed id
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Secondary reference #5
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Title
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Structural evidence for gene duplication in the evolution of the acid proteases.
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Authors
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J.Tang,
M.N.James,
I.N.Hsu,
J.A.Jenkins,
T.L.Blundell.
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Ref.
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Nature, 1978,
271,
618-621.
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PubMed id
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Secondary reference #6
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Title
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Homology among acid proteases: comparison of crystal structures at 3a resolution of acid proteases from rhizopus chinensis and endothia parasitica.
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Authors
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E.Subramanian,
I.D.Swan,
M.Liu,
D.R.Davies,
J.A.Jenkins,
I.J.Tickle,
T.L.Blundell.
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Ref.
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Proc Natl Acad Sci U S A, 1977,
74,
556-559.
[DOI no: ]
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PubMed id
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Secondary reference #7
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Title
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X-Ray analysis and circular dichroism of the acid protease from endothia parasitica and chymosin.
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Authors
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J.Jenkins,
I.Tickle,
T.Sewell,
L.Ungaretti,
A.Wollmer,
T.Blundell.
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Ref.
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Adv Exp Med Biol, 1977,
95,
43-60.
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PubMed id
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