4EN4

Crystal Structure of the Ternary Human PL Kinase-Ginkgotoxin-MgATP Complex

Summary for 4EN4

• Entry DOI: 10.2210/pdb4en4/pdb
• Related: 2YXU 4EOH
• Descriptor: Pyridoxal kinase, MAGNESIUM ION, SODIUM ION, ... (9 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O00764
• Total number of polymer chains: 2
• Total formula weight: 73622.29

Authors

Safo, M.K.,Musayev, F.N.,Gandhi, A.K. (deposition date: 2012-04-12, release date: 2012-05-02, Last modification date: 2024-03-13)

Primary citation

Gandhi, A.K.,Desai, J.V.,Ghatge, M.S.,di Salvo, M.L.,Di Biase, S.,Danso-Danquah, R.,Musayev, F.N.,Contestabile, R.,Schirch, V.,Safo, M.K.
Crystal structures of human pyridoxal kinase in complex with the neurotoxins, ginkgotoxin and theophylline: insights into pyridoxal kinase inhibition.
Plos One, 7:e40954-e40954, 2012

PubMed Abstract: Several drugs and natural compounds are known to be highly neurotoxic, triggering epileptic convulsions or seizures, and causing headaches, agitations, as well as other neuronal symptoms. The neurotoxic effects of some of these compounds, including theophylline and ginkgotoxin, have been traced to their inhibitory activity against human pyridoxal kinase (hPL kinase), resulting in deficiency of the active cofactor form of vitamin B₆, pyridoxal 5'-phosphate (PLP). Pyridoxal (PL), an inactive form of vitamin B₆ is converted to PLP by PL kinase. PLP is the B₆ vitamer required as a cofactor for over 160 enzymatic activities essential in primary and secondary metabolism. We have performed structural and kinetic studies on hPL kinase with several potential inhibitors, including ginkgotoxin and theophylline. The structural studies show ginkgotoxin and theophylline bound at the substrate site, and are involved in similar protein interactions as the natural substrate, PL. Interestingly, the phosphorylated product of ginkgotoxin is also observed bound at the active site. This work provides insights into the molecular basis of hPL kinase inhibition and may provide a working hypothesis to quickly screen or identify neurotoxic drugs as potential hPL kinase inhibitors. Such adverse effects may be prevented by administration of an appropriate form of vitamin B₆, or provide clues of how to modify these drugs to help reduce their hPL kinase inhibitory effects.

PubMed: 22879864
DOI: 10.1371/journal.pone.0040954

Experimental method

X-RAY DIFFRACTION (2.15 Å)