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PDBsum entry 4a28
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Motor protein
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PDB id
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4a28
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PDB id:
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| Name: |
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Motor protein
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Title:
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Eg5-2
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Structure:
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Kinesin-like protein kif11. Chain: a, b. Fragment: motor domain, residues 1-368. Synonym: kinesin-like protein 1, kinesin-like spindle protein hksp, kinesin-related motor protein eg5, eg5-2, thyroid receptor- interacting protein 5, tr-interacting protein 5, trip-5. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plyss.
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Resolution:
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2.55Å
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R-factor:
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0.184
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R-free:
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0.264
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Authors:
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S.K.Talapatra,F.Kozielski
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Key ref:
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S.K.Talapatra
et al.
(2013).
Mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism.
J Med Chem,
56,
6317-6329.
PubMed id:
DOI:
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Date:
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22-Sep-11
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Release date:
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31-Oct-12
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PROCHECK
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Headers
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References
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P52732
(KIF11_HUMAN) -
Kinesin-like protein KIF11 from Homo sapiens
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Seq:
Struc:
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1056 a.a.
332 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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J Med Chem
56:6317-6329
(2013)
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PubMed id:
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Mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism.
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S.K.Talapatra,
N.G.Anthony,
S.P.Mackay,
F.Kozielski.
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ABSTRACT
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Development of drug resistance during cancer chemotherapy is one of the major
causes of chemotherapeutic failure for the majority of clinical agents. The aim
of this study was to investigate the underlying molecular mechanism of
resistance developed by the mitotic kinesin Eg5 against the potent
second-generation ispinesib analogue SB743921 (1), a phase I/II clinical
candidate. Biochemical and biophysical data demonstrate that point mutations in
the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold.
Surprisingly, the structures of wild-type and mutant Eg5 in complex with 1
display no apparent structural changes in the binding configuration of the drug
candidate. Furthermore, ITC and modeling approaches reveal that resistance to 1
is not through conventional steric effects at the binding site but through
reduced flexibility and changes in energy fluctuation pathways through the
protein that influence its function. This is a phenomenon we have called
"resistance by allostery".
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Links
