4HKP

Crystal structure of human orotidine 5'-monophosphate decarboxylase complexed with CMP-N3-oxide

Summary for 4HKP

• Entry DOI: 10.2210/pdb4hkp/pdb
• Related: 4HIB
• Descriptor: Uridine 5'-monophosphate synthase, GLYCEROL, 5-hydroxycytidine 5'-(dihydrogen phosphate), ... (5 entities in total)
• Functional Keywords: alpha-beta barrel, decarboxylase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69678.46

Authors

To, T.K.,Kotra, L.P.,Pai, E.F. (deposition date: 2012-10-15, release date: 2012-11-14, Last modification date: 2024-02-28)

Primary citation

Purohit, M.K.,Poduch, E.,Wei, L.W.,Crandall, I.E.,To, T.,Kain, K.C.,Pai, E.F.,Kotra, L.P.
Novel cytidine-based orotidine-5'-monophosphate decarboxylase inhibitors with an unusual twist.
J.Med.Chem., 55:9988-9997, 2012

PubMed Abstract: Orotidine-5'-monophosphate decarboxylase (ODCase) is an interesting enzyme with an unusual catalytic activity and a potential drug target in Plasmodium falciparum, which causes malaria. ODCase has been shown to exhibit unusual and interesting interactions with a variety of nucleotide ligands. Cytidine-5'-monophosphate (CMP) is a poor ligand of ODCase, and CMP binds to the active site of ODCase with an unusual orientation and conformation. We designed N3- and N4-modified CMP derivatives as novel ligands to ODCase. These novel CMP derivatives and their corresponding nucleosides were evaluated against Plasmodium falciparum ODCase and parasitic cultures, respectively. These derivatives exhibited improved inhibition of the enzyme catalytic activity, displayed interesting binding conformations and unusual molecular rearrangements of the ligands. These findings with the modified CMP nucleotides underscored the potential of transformation of poor ligands to ODCase into novel inhibitors of this drug target.

PubMed: 22991951
DOI: 10.1021/jm301176r

Experimental method

X-RAY DIFFRACTION (1.75 Å)