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PDBsum entry 4r5m
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Oxidoreductase
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PDB id
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4r5m
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Crystal structure of vc-aspartate beta-semialdehyde-dehydrogenase with NADP and 4-nitro-2-phosphono-benzoic acid
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Structure:
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Aspartate-semialdehyde dehydrogenase 1. Chain: a, b. Synonym: asa dehydrogenase 1, asadh 1, aspartate-beta-semialdehyde dehydrogenase 1. Engineered: yes
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Source:
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Vibrio cholerae o1. Organism_taxid: 243277. Strain: atcc 39315. Gene: asd1, q9kqg2, vc_2036. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.89Å
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R-factor:
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0.171
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R-free:
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0.197
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Authors:
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A.G.Pavlovsky,B.Thangavelu,P.Bhansali,R.E.Viola
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Key ref:
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A.G.Pavlovsky
et al.
(2014).
A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway.
Acta Crystallogr D Biol Crystallogr,
70,
3244-3252.
PubMed id:
DOI:
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Date:
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21-Aug-14
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Release date:
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10-Dec-14
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PROCHECK
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Headers
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References
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Q9KQG2
(DHAS1_VIBCH) -
Aspartate-semialdehyde dehydrogenase 1 from Vibrio cholerae serotype O1 (strain ATCC 39315 / El Tor Inaba N16961)
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Seq:
Struc:
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370 a.a.
369 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.1.2.1.11
- aspartate-semialdehyde dehydrogenase.
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Pathway:
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Lysine biosynthesis (early stages)
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Reaction:
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L-aspartate 4-semialdehyde + phosphate + NADP+ = 4-phospho-L-aspartate + NADPH + H+
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L-aspartate 4-semialdehyde
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+
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phosphate
Bound ligand (Het Group name = )
corresponds exactly
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+
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NADP(+)
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=
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4-phospho-L-aspartate
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+
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NADPH
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Acta Crystallogr D Biol Crystallogr
70:3244-3252
(2014)
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PubMed id:
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A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway.
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A.G.Pavlovsky,
B.Thangavelu,
P.Bhansali,
R.E.Viola.
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ABSTRACT
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The aspartate pathway is essential for the production of the amino acids
required for protein synthesis and of the metabolites needed in bacterial
development. This pathway also leads to the production of several classes of
quorum-sensing molecules that can trigger virulence in certain microorganisms.
The second enzyme in this pathway, aspartate β-semialdehyde dehydrogenase
(ASADH), is absolutely required for bacterial survival and has been targeted for
the design of selective inhibitors. Fragment-library screening has identified a
new set of inhibitors that, while they do not resemble the substrates for this
reaction, have been shown to bind at the active site of ASADH. Structure-guided
development of these lead compounds has produced moderate inhibitors of the
target enzyme, with some selectivity observed between the Gram-negative and
Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and
derivatives have not yet achieved the expected enhanced affinity. Structural
characterization of these enzyme-inhibitor complexes has provided detailed
explanations for the barriers that interfere with optimal binding. Despite
binding in the same active-site region, significant changes are observed in the
orientation of these bound inhibitors that are caused by relatively modest
structural alterations. Taken together, these studies present a cautionary tale
for issues that can arise in the systematic approach to the modification of lead
compounds that are being used to develop potent inhibitors.
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Links
