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PDBsum entry 4l23
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Signaling protein/transferase/inhibitor
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PDB id
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4l23
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References listed in PDB file
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Key reference
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Title
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Crystal structures of pi3kα complexed with pi103 and its derivatives: new directions for inhibitors design.
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Authors
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Y.Zhao,
X.Zhang,
Y.Chen,
S.Lu,
Y.Peng,
X.Wang,
C.Guo,
A.Zhou,
J.Zhang,
Y.Luo,
Q.Shen,
J.Ding,
L.Meng,
J.Zhang.
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Ref.
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Acs Med Chem Lett, 2014,
5,
138-142.
[DOI no: ]
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PubMed id
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Abstract
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The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles
in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently
found in a wide variety of human cancers, validating it as a promising target
for cancer therapy. We determined the crystal structure of the human
PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure,
substitution at the R1 position of the phenol portion of PI103 was demonstrated
to improve binding affinity via forming a new H-bond with Lys802 at the bottom
of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d
complex revealed that the flexibility of Lys802 can also induce additional space
at the catalytic site for further modification. Thus, these crystal structures
provide a molecular basis for the strong and specific interactions and
demonstrate the important role of Lys802 in the design of novel PI3Kα
inhibitors.
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