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PDBsum entry 5o2s
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Signaling protein
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PDB id
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5o2s
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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 and functional characterization of a darpin which inhibits ras nucleotide exchange.
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Authors
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S.Guillard,
P.Kolasinska-Zwierz,
J.Debreczeni,
J.Breed,
J.Zhang,
N.Bery,
R.Marwood,
J.Tart,
R.Overman,
P.Stocki,
B.Mistry,
C.Phillips,
T.Rabbitts,
R.Jackson,
R.Minter.
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Ref.
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Nat Commun, 2017,
8,
16111.
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PubMed id
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Abstract
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Ras mutations are the oncogenic drivers of many human cancers and yet there are
still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide
exchange is a promising new approach but better understanding of this mechanism
of action is needed. Here we describe an antibody mimetic, DARPin K27, which
inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive
Ras GDP form with a Kdof 4 nM and structural studies support its
selectivity for inactive Ras. Intracellular expression of K27 significantly
reduces the amount of active Ras, inhibits downstream signalling, in particular
the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116
cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing
consistent effects across different isoforms of Ras, including wild-type and
oncogenic mutant forms.
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