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PDBsum entry 3b9m
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Lipid binding protein
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PDB id
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3b9m
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References listed in PDB file
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Key reference
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Title
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A new drug binding subsite on human serum albumin and drug-Drug interaction studied by X-Ray crystallography.
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Authors
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L.Zhu,
F.Yang,
L.Chen,
E.J.Meehan,
M.Huang.
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Ref.
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J Struct Biol, 2008,
162,
40-49.
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PubMed id
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Abstract
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3'-Azido-3'-deoxythymidine (AZT) is the first clinically effective drug for the
treatment of human immunodeficiency virus infection. The drug interaction with
human serum albumin (HSA) has been an important component in understanding its
mechanism of action, especially in drug distribution and in drug-drug
interaction on HSA in the case of multi-drug therapy. We present here crystal
structures of a ternary HSA-Myr-AZT complex and a quaternary HSA-Myr-AZT-SAL
complex (Myr, myristate; SAL, salicylic acid). From this study, a new drug
binding subsite on HSA Sudlow site 1 was identified. The presence of fatty acid
is needed for the creation of this subsite due to fatty acid induced
conformational changes of HSA. Thus, the Sudlow site 1 of HSA can be divided
into three non-overlapped subsites: a SAL subsite, an indomethacin subsite and
an AZT subsite. Binding of a drug to HSA often influences simultaneous binding
of other drugs. From the HSA-Myr-AZT-SAL complex structure, we observed the
coexistence of two drugs (AZT and SAL) in Sudlow site 1 and the competition
between these two drugs in subdomain IB. These results provide new structural
information on HSA-drug interaction and drug-drug interaction on HSA.
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Secondary reference #1
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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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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
reproduced from the cited reference
with permission from Elsevier
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Secondary reference #2
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Title
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Effect of human serum albumin on drug metabolism: structural evidence of esterase activity of human serum albumin.
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Authors
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F.Yang,
C.Bian,
L.Zhu,
G.Zhao,
Z.Huang,
M.Huang.
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Ref.
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J Struct Biol, 2007,
157,
348-355.
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PubMed id
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Secondary reference #3
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Title
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Atomic structure and chemistry of human serum albumin.
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Authors
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X.M.He,
D.C.Carter.
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Ref.
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Nature, 1992,
358,
209-215.
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PubMed id
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