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PDBsum entry 2bxe
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Transport protein
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PDB id
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2bxe
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References listed in PDB file
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Key reference
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Title
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Structural basis of the drug-Binding specificity of human serum albumin.
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Authors
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J.Ghuman,
P.A.Zunszain,
I.Petitpas,
A.A.Bhattacharya,
M.Otagiri,
S.Curry.
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Ref.
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J Mol Biol, 2005,
353,
38-52.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably
wide range of drugs, thereby restricting their free, active concentrations. The
problem of overcoming the binding affinity of lead compounds for HSA represents
a major challenge in drug development. Crystallographic analysis of 17 different
complexes of HSA with a wide variety of drugs and small-molecule toxins reveals
the precise architecture of the two primary drug-binding sites on the protein,
identifying residues that are key determinants of binding specificity and
illuminating the capacity of both pockets for flexible accommodation. Numerous
secondary binding sites for drugs distributed across the protein have also been
identified. The binding of fatty acids, the primary physiological ligand for the
protein, is shown to alter the polarity and increase the volume of drug site 1.
These results clarify the interpretation of accumulated drug binding data and
provide a valuable template for design efforts to modulate the interaction with
HSA.
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Figure 2.
Figure 2. Overview of HSA structure and omit maps. (a)
Structure of HSA-diazepam. The protein is colour-coded by
subdomain using a scheme that is maintained throughout. The
diazepam is depicted in space-filling representation
colour-coded by atom-type: carbon, pink; oxygen, red; nitrogen,
blue; chlorine, gr. The rotated view on the right shows drug
site 2 in the same orientation as drug site 1 in (c). (b) F[o]
-F[c] simulated annealing omit map calculated in CNS50 with the
diazepam molecule omitted from the phasing model and contoured
at 2.75s. (c) Structure of HSA-myristate-phenylbutazone. Fatty
acid molecules and phenylbutazone are depicted in space-filling
representation with carbon atoms coloured grey and mid-blue,
respectively. (d) F[o] -F[c] simulated annealing omit map
calculated with the phenylbutazone molecule omitted from the
phasing model and contoured at 2.75s. All Figures were prepared
using PyMol.55
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Figure 7.
Figure 7. Summary of the ligand binding capacity of HSA as
defined by crystallographic studies to date. Ligands are
depicted in space-filling representation; oxygen atoms are
coloured red; all other atoms in fatty acids (myristic acid),
other endogenous ligands (hemin, thyroxin) and drugs are
coloured dark-grey, light grey and orange, respectively.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
353,
38-52)
copyright 2005.
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