4BXN

Eg5(WT) complex

Summary for 4BXN

• Entry DOI: 10.2210/pdb4bxn/pdb
• Descriptor: KINESIN-LIKE PROTEIN KIF11, ADENOSINE-5'-DIPHOSPHATE, CADMIUM ION, ... (6 entities in total)
• Functional Keywords: motor protein, mitosis
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 86756.35

Authors

Talapatra, S.K.,Anthony, N.G.,Mackay, S.P.,Kozielski, F. (deposition date: 2013-07-15, release date: 2013-07-31, Last modification date: 2024-02-07)

Primary citation

Talapatra, S.K.,Anthony, N.G.,Mackay, S.P.,Kozielski, F.
The Mitotic Kinesin Eg5 Overcomes Inhibition to the Phase I/II Clinical Candidate Sb743921 by an Allosteric Resistance Mechanism.
J.Med.Chem., 56:6317-, 2013

PubMed Abstract: 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".

PubMed: 23875972
DOI: 10.1021/JM4006274

Experimental method

X-RAY DIFFRACTION (2.793 Å)