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PDBsum entry 1mfh
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Transport protein
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PDB id
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1mfh
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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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Design of specific peptide inhibitors for group i phospholipase a2: structure of a complex formed between phospholipase a2 from naja naja sagittifera (group i) and a designed peptide inhibitor val-Ala-Phe-Arg-Ser (vafrs) at 1.9 a resolution reveals unique features.
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Authors
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R.K.Singh,
P.Vikram,
J.Makker,
T.Jabeen,
S.Sharma,
S.Dey,
P.Kaur,
A.Srinivasan,
T.P.Singh.
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Ref.
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Biochemistry, 2003,
42,
11701-11706.
[DOI no: ]
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PubMed id
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Abstract
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Phospholipase A(2) (PLA(2)) (E. C. 3.1.1.4) is a common enzyme in the two-way
cascade mechanism leading to the production of proinflammatory compounds known
as eicosanoids. The binding of phospholipase A(2) to the membrane surface and
hydrolysis of phospholipids are thought to involve the formation of a
hydrophobic channel into which a single substrate molecule diffuses before its
cleavage. To regulate the production of proinflammatory compounds, a specific
peptide inhibitor Val-Ala-Phe-Arg-Ser (VAFRS) for the group I PLA(2) enzymes has
been designed and synthesized. PLA(2) was isolated from Indian cobra (Naja naja
sagittifera) venom and purified to homogeneity. The binding studies indicated
the K(i) value of 1.02 +/- 0.10 x 10(-8) M. The purified PLA(2) samples and the
designed inhibitor VAFRS were cocrystallized. The crystal structure of the
complex was determined and refined to 1.9 A resolution. The peptide binds to
PLA(2) at the active site and fills the hydrophobic channel completely. However,
its placement with respect to the channel is in the opposite direction as
compared to those observed in group II PLA(2)'s. Furthermore, the predominant
intermolecular interactions involve strong electrostatic interactions between
the side chains of peptide Arg and Asp 49 of PLA(2) together with a number of
van der Waals interactions with other residues. A good number of observed
interactions between the peptide and the protein indicate the significance of a
structure-based drug design approach. The novel factor in the present sequence
of the peptide is related to the introduction of a positively charged residue at
the C-terminal part of the peptide.
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