1YGJ

Crystal Structure of Pyridoxal Kinase in Complex with Roscovitine and Derivatives

Summary for 1YGJ

• Entry DOI: 10.2210/pdb1ygj/pdb
• Related: 1YGK
• Descriptor: Pyridoxal kinase, (2R)-2-({6-[BENZYL(METHYL)AMINO]-9-ISOPROPYL-9H-PURIN-2-YL}AMINO)BUTAN-1-OL (3 entities in total)
• Functional Keywords: alpha-beta structure, n6-methyl-(r)-roscovitine complex, transferase
• Biological source: Ovis aries (sheep)
• Cellular location: Cytoplasm: P82197
• Total number of polymer chains: 1
• Total formula weight: 35229.36

Authors

Tang, L.,Li, M.-H.,Cao, P.,Wang, F.,Chang, W.-R.,Bach, S.,Reinhardt, J.,Ferandin, Y.,Koken, M.,Galons, H.,Wan, Y.,Gray, N.,Meijer, L.,Jiang, T.,Liang, D.-C. (deposition date: 2005-01-05, release date: 2005-07-05, Last modification date: 2024-03-13)

Primary citation

Tang, L.,Li, M.-H.,Cao, P.,Wang, F.,Chang, W.-R.,Bach, S.,Reinhardt, J.,Ferandin, Y.,Galons, H.,Wan, Y.,Gray, N.,Meijer, L.,Jiang, T.,Liang, D.-C.
Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives
J.Biol.Chem., 280:31220-31229, 2005

PubMed Abstract: 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.

PubMed: 15985434
DOI: 10.1074/jbc.M500805200

Experimental method

X-RAY DIFFRACTION (2.7 Å)