J. Biol. Chem. 280, 31208-31219.
Tang, L., Li, M.H., Cao,
P., Wang, F., Chang, W.R., Bach, S., Reinhardt, J., Koken, M., Galons, H.,
Wan, Y., Gray, N., Meijer, L., Jiang. T. and Liang, D.C.
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.
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