PDBsum entry 2x7c

Cell cycle

PDB id: 2x7c

Contents

Protein chains

332 a.a. *

Ligands

ADP ×2

KZ9 ×2

Metals

_MG ×3

Waters ×683

* Residue conservation analysis

PDB id:

2x7c

Name:

Cell cycle

Title:

Crystal structure of human kinesin eg5 in complex with (s)-enastron

Structure:

Kinesin-like protein kif11. Chain: a, b. Fragment: motor domain, residues 1-368. Synonym: kinesin-related motor protein eg5, kinesin-like spindle protein hksp, thyroid receptor-interacting protein 5, kinesin-like protein 1, trip-5. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.90Å R-factor: 0.167 R-free: 0.232

Authors:

H.Y.K.Kaan,V.Ulaganathan,O.Rath,C.Laggner,H.Prokopcova,D.Dallinger, C.O.Kappe,F.Kozielski

Key ref:

H.Y.Kaan et al. (2010). Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol. J Med Chem, 53, 5676-5683. PubMed id: 20597485

Date:

26-Feb-10 Release date: 14-Jul-10

Protein chains

P52732  (KIF11_HUMAN) -  Kinesin-like protein KIF11 from Homo sapiens

Seq: 1056 a.a.

Struc: 332 a.a.

J Med Chem 53:5676-5683 (2010)

PubMed id: 20597485

Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol.

H.Y.Kaan, V.Ulaganathan, O.Rath, H.Prokopcová, D.Dallinger, C.O.Kappe, F.Kozielski.

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.