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PDBsum entry 3pmj
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Hydrolase/hydrolase inhibitor
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PDB id
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3pmj
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Bovine trypsin variant x(tripleile227) in complex with small molecule inhibitor
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Structure:
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Cationic trypsin. Chain: a. Synonym: beta-trypsin, alpha-trypsin chain 1, alpha-trypsin chain 2. Engineered: yes. Mutation: yes
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Source:
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Bos taurus. Bovine,cow,domestic cattle,domestic cow. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.45Å
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R-factor:
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0.177
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R-free:
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0.230
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Authors:
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A.Tziridis,P.Neumann,P.Kolenko,M.T.Stubbs
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Key ref:
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A.Tziridis
et al.
(2014).
Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.
Biol Chem,
395,
891-903.
PubMed id:
DOI:
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Date:
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17-Nov-10
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Release date:
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23-Nov-11
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PROCHECK
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Headers
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References
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P00760
(TRY1_BOVIN) -
Serine protease 1 from Bos taurus
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Seq:
Struc:
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246 a.a.
223 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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*
PDB and UniProt seqs differ
at 8 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.21.4
- trypsin.
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Reaction:
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Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.
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DOI no:
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Biol Chem
395:891-903
(2014)
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PubMed id:
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Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.
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A.Tziridis,
D.Rauh,
P.Neumann,
P.Kolenko,
A.Menzel,
U.Bräuer,
C.Ursel,
P.Steinmetzer,
J.Stürzebecher,
A.Schweinitz,
T.Steinmetzer,
M.T.Stubbs.
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ABSTRACT
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Abstract A high-resolution crystallographic structure determination of a
protein-ligand complex is generally accepted as the 'gold standard' for
structure-based drug design, yet the relationship between structure and affinity
is neither obvious nor straightforward. Here we analyze the interactions of a
series of serine proteinase inhibitors with trypsin variants onto which the
ligand-binding site of factor Xa has been grafted. Despite conservative
mutations of only two residues not immediately in contact with ligands (second
shell residues), significant differences in the affinity profiles of the
variants are observed. Structural analyses demonstrate that these are due to
multiple effects, including differences in the structure of the binding site,
differences in target flexibility and differences in inhibitor binding modes.
The data presented here highlight the myriad competing microscopic processes
that contribute to protein-ligand interactions and emphasize the difficulties in
predicting affinity from structure.
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Links
