Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives.
Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.
Lin
L
Tang
Ming-Hui
MH
Li
Peng
P
Cao
Feng
F
Wang
Wen-Rui
WR
Chang
Stéphane
S
Bach
Jens
J
Reinhardt
Yoan
Y
Ferandin
Hervé
H
Galons
Yongqin
Y
Wan
Nathanael
N
Gray
Laurent
L
Meijer
Tao
T
Jiang
Dong-Cai
DC
Liang
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry* / Q000378:metabolism; D011731:Pyridoxal Kinase / Q000737:chemistry* / Q000378:metabolism; D000077546:Roscovitine; D013552:Swine
D008024:Ligands; D046911:Macromolecular Substances; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D011731:Pyridoxal Kinase