PDBsum entry 2ieh

Hydrolase

PDB id: 2ieh

Contents

Protein chains

334 a.a. *

Ligands

ADP ×2

MOY ×2

PG4

Metals

_MG ×2

__K

_CL

Waters ×214

* Residue conservation analysis

PDB id:

2ieh

Name:

Hydrolase

Title:

Crystal structure of human kinesin eg5 in complex with (r)-mon97, a new monastrol-based inhibitor that binds as (r)-enantiomer

Structure:

Kinesin-like protein kif11. Chain: a, b. Fragment: motor domain of human kinesin eg5. Synonym: kinesin-related motor protein eg5, kinesin-like spindle protein hksp, thyroid receptor-interacting protein 5, trip5, kinesin- like protein 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kif11, eg5, knsl1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.70Å R-factor: 0.234 R-free: 0.281

Authors:

I.Garcia-Saez,F.Kozielski

Key ref:

I.Garcia-Saez et al. (2007). Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. J Biol Chem, 282, 9740-9747. PubMed id: 17251189 DOI: 10.1074/jbc.M608883200

Date:

19-Sep-06 Release date: 23-Jan-07

Protein chains

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

Seq: 1056 a.a.

Struc: 334 a.a.

Enzyme reactions

• Enzyme class: E.C.3.6.4.4 - Transferred entry: 5.6.1.3.
• Reaction: ATP + H₂O = ADP + phosphate

ATP + H(2)O = ADP (Bound ligand (Het Group name = ADP) corresponds exactly) + phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M608883200

J Biol Chem 282:9740-9747 (2007)

PubMed id: 17251189

Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.

I.Garcia-Saez, S.DeBonis, R.Lopez, F.Trucco, B.Rousseau, P.Thuéry, F.Kozielski.

ABSTRACT

Drugs that target mitotic spindle proteins have been proven useful for tackling tumor growth. Eg5, a kinesin-5 family member, represents a potential target, since its inhibition leads to prolonged mitotic arrest through the activation of the mitotic checkpoint and apoptotic cell death. Monastrol, a specific dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the biologically active compound in vitro and in cell-based assays. Here, we solved the crystal structure (2.7A) of the complex between human Eg5 and a new keto derivative of monastrol (named mon-97), a potent antimitotic inhibitor. Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer. The absolute configuration of this more active (R)-enantiomer has been unambiguously determined via chemical correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays) and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However, the difference was large enough for the protein to select the (R)- over the (S)-enantiomer. Taken together, these results show that in this new monastrol family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This considerably broadens the alternatives for rational drug design.

Selected figure(s)

Figure 1.
FIGURE 1. Chemical structures of monastrol (A) and mon-97 (B).

Figure 4.
FIGURE 4. Schematic view of the contacts between (R)-mon-97 (A) and (S)-monastrol (B) and residues of the Eg5 inhibitor-binding pocket using the program LIGPLOT (24). Hydrophobic contacts ( 3.9 Å) and hydrogen bonds are depicted with red and green dashed lines, respectively. The ethyl group of (S)-monastrol points toward the solvent, whereas in the (R)-mon-97 structure the phenyl group that substitutes the ethyl group is buried in the hydrophobic pocket.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 9740-9747) copyright 2007.

Figures were selected by an automated process.