2X7D

Crystal structure of human kinesin Eg5 in complex with (S)-dimethylenastron

Summary for 2X7D

• Entry DOI: 10.2210/pdb2x7d/pdb
• Related: 1II6 1Q0B 1X88 1YRS 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WOG 2X2R 2X7C 2X7E
• Descriptor: KINESIN-LIKE PROTEIN KIF11, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: microtubule, atp-binding, motor protein, cell division, mitosis, inhibitor, cell cycle, nucleotide-binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 2
• Total formula weight: 83667.57

Authors

Kaan, H.Y.K.,Ulaganathan, V.,Rath, O.,Laggner, C.,Prokopcova, H.,Dallinger, D.,Kappe, C.O.,Kozielski, F. (deposition date: 2010-02-26, release date: 2010-07-14, Last modification date: 2023-12-20)

Primary citation

Kaan, H.Y.K.,Ulaganathan, V.,Rath, O.,Prokopcova, H.,Dallinger, D.,Kappe, C.O.,Kozielski, F.
Structural Basis for Inhibition of Eg5 by Dihydropyrimidines: Stereoselectivity of Antimitotic Inhibitors Enastron, Dimethylenastron and Fluorastrol.
J.Med.Chem., 53:5676-, 2010

PubMed Abstract: Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.

PubMed: 20597485
DOI: 10.1021/JM100421N

Experimental method

X-RAY DIFFRACTION (2.3 Å)