4A1Z

Eg5-1

Summary for 4A1Z

• Entry DOI: 10.2210/pdb4a1z/pdb
• Related: 1II6 1Q0B 1X88 1YRS 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WOG 2X2R 2X7C 2X7D 2X7E 2XAE
• Descriptor: KINESIN-LIKE PROTEIN KIF11, MAGNESIUM ION, NITRATE ION, ... (5 entities in total)
• Functional Keywords: motor protein
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 2
• Total formula weight: 83106.27

Authors

Talapatra, S.K.,Kozielski, F. (deposition date: 2011-09-20, release date: 2012-10-31, Last modification date: 2023-12-20)

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 (2.8 Å)