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PDBsum entry 1msm
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Hydrolase/hydrolase inhibitor
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PDB id
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1msm
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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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A structural and thermodynamic escape mechanism from a drug resistant mutation of the HIV-1 protease.
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Authors
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S.Vega,
L.W.Kang,
A.Velazquez-Campoy,
Y.Kiso,
L.M.Amzel,
E.Freire.
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Ref.
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Proteins, 2004,
55,
594-602.
[DOI no: ]
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PubMed id
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Abstract
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The efficacy of HIV-1 protease inhibition therapies is often compromised by the
appearance of mutations in the protease molecule that lower the binding affinity
of inhibitors while maintaining viable catalytic activity and substrate
affinity. The V82F/I84V double mutation is located within the binding site
cavity and affects all protease inhibitors in clinical use. KNI-764, a
second-generation inhibitor currently under development, maintains significant
potency against this mutation by entropically compensating for enthalpic losses,
thus minimizing the loss in binding affinity. KNI-577 differs from KNI-764 by a
single functional group critical to the inhibitor response to the protease
mutation. This single difference changes the response of the two inhibitors to
the mutation by one order of magnitude. Accordingly, a structural understanding
of the inhibitor response will provide important guidelines for the design of
inhibitors that are less susceptible to mutations conveying drug resistance. The
structures of the two compounds bound to the wild type and V82F/I84V HIV-1
protease have been determined by X-ray crystallography at 2.0 A resolution. The
presence of two asymmetric functional groups, linked by rotatable bonds to the
inhibitor scaffold, allows KNI-764 to adapt to the mutated binding site cavity
more readily than KNI-577, with a single asymmetric group. Both inhibitors lose
about 2.5 kcal/mol in binding enthalpy when facing the drug-resistant mutant
protease; however KNI-764 gains binding entropy while KNI-577 loses binding
entropy. The gain in binding entropy by KNI-764 accounts for its low
susceptibility to the drug-resistant mutation. The heat capacity change
associated with binding becomes more negative when KNI-764 binds to the mutant
protease, consistent with increased desolvation. With KNI-577, the opposite
effect is observed. Structurally, the crystallographic B factors increase for
KNI-764 when it is bound to the drug-resistant mutant. The opposite is observed
for KNI-577. Consistent with these observations, it appears that KNI-764 is able
to gain binding entropy by a two-fold mechanism: it gains solvation entropy by
burying itself deeper within the binding pocket and gains conformational entropy
by losing interaction with the protease.
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Figure 2.
Figure 2. The chemical structure of KNI-577 (left) and KNI-764
(right). Both inhibitors share the same allophenyl-norstatine
scaffold at the P1 position (red) and the same functional groups
at the P2 (blue) and P1  positions
(green). The only difference is at the P2 position
(magenta).
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Figure 4.
Figure 4. Superposition of the complexes of KNI-764 (left) and
KNI-577 (right) bound to wild-type (cyan) and double mutant
(purple) protease.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2004,
55,
594-602)
copyright 2004.
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