4AP0

The mitotic kinesin Eg5 in complex with Mg-ADP and ispinesib

Summary for 4AP0

• Entry DOI: 10.2210/pdb4ap0/pdb
• Related: 1II6 1Q0B 1X88 1YRS 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WOG 2X2R 2X7C 2X7D 2X7E 2XAE 4A1Z 4A28 4A2T 4A50 4A51 4A5Y
• Descriptor: KINESIN-LIKE PROTEIN KIF11, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: motor protein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 4
• Total formula weight: 168925.97

Authors

Schuettelkopf, A.W.,Talapatra, S.K.,Kozielski, F. (deposition date: 2012-03-30, release date: 2012-09-26, Last modification date: 2023-12-20)

Primary citation

Talapatra, S.K.,Schuettelkopf, A.W.,Kozielski, F.
The Structure of the Ternary Eg5-Adp-Ispinesib Complex
Acta Crystallogr.,Sect.D, 68:1311-, 2012

PubMed Abstract: The human kinesin Eg5 is responsible for bipolar spindle formation during early mitosis. Inhibition of Eg5 triggers the formation of monoastral spindles, leading to mitotic arrest that eventually causes apoptosis. There is increasing evidence that Eg5 constitutes a potential drug target for the development of cancer chemotherapeutics. The most advanced Eg5-targeting agent is ispinesib, which exhibits potent antitumour activity and is currently in multiple phase II clinical trials. In this study, the crystal structure of the Eg5 motor domain in complex with ispinesib, supported by kinetic and thermodynamic binding data, is reported. Ispinesib occupies the same induced-fit pocket in Eg5 as other allosteric inhibitors, making extensive hydrophobic interactions with the protein. The data for the Eg5-ADP-ispinesib complex suffered from pseudo-merohedral twinning and revealed translational noncrystallographic symmetry, leading to challenges in data processing, space-group assignment and structure solution as well as in refinement. These complications may explain the lack of available structural information for this important agent and its analogues. The present structure represents the best interpretation of these data based on extensive data-reduction, structure-solution and refinement trials.

PubMed: 22993085
DOI: 10.1107/S0907444912027965

Experimental method

X-RAY DIFFRACTION (2.594 Å)