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Title
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Role of interfacial water molecules in proline-rich ligand recognition by the Src homology 3 domain of Abl.
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Authors
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A.Palencia,
A.Camara-Artigas,
M.T.Pisabarro,
J.C.Martinez,
I.Luque.
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Ref.
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J Biol Chem, 2010,
285,
2823-2833.
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PubMed id
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Abstract
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The interaction of Abl-Src homology 3 domain (SH3) with the high affinity
peptide p41 is the most notable example of the inconsistency existing between
the currently accepted description of SH3 complexes and their binding
thermodynamic signature. We had previously hypothesized that the presence of
interfacial water molecules is partially responsible for this thermodynamic
behavior. We present here a thermodynamic, structural, and molecular dynamics
simulation study of the interaction of p41 with Abl-SH3 and a set of mutants
designed to alter the water-mediated interaction network. Our results provide a
detailed description of the dynamic properties of the interfacial water
molecules and a molecular interpretation of the thermodynamic effects elicited
by the mutations in terms of the modulation of the water-mediated hydrogen bond
network. In the light of these results, a new dual binding mechanism is proposed
that provides a better description of proline-rich ligand recognition by Abl-SH3
and that has important implications for rational design.
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