2G1Q

crystal structure of KSP in complex with inhibitor 9h

Summary for 2G1Q

• Entry DOI: 10.2210/pdb2g1q/pdb
• Descriptor: Kinesin-like protein KIF11, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: ksp, ksp-inhibitor complex, cell cycle
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 2
• Total formula weight: 83787.05

Authors

Yan, Y. (deposition date: 2006-02-14, release date: 2006-10-03, Last modification date: 2024-02-14)

Primary citation

Cox, C.D.,Torrent, M.,Breslin, M.J.,Mariano, B.J.,Whitman, D.B.,Coleman, P.J.,Buser, C.A.,Walsh, E.S.,Hamilton, K.,Schaber, M.D.,Lobell, R.B.,Tao, W.,South, V.J.,Kohl, N.E.,Yan, Y.,Kuo, L.C.,Prueksaritanont, T.,Slaughter, D.E.,Li, C.,Mahan, E.,Lu, B.,Hartman, G.D.
Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP.
Bioorg.Med.Chem.Lett., 16:3175-3179, 2006

PubMed Abstract: Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.

PubMed: 16603356
DOI: 10.1016/j.bmcl.2006.03.040

Experimental method

X-RAY DIFFRACTION (2.51 Å)