3C3C

Crystal Structure of human phosphoglycerate kinase bound to 3-phosphoglycerate and L-CDP

Summary for 3C3C

• Entry DOI: 10.2210/pdb3c3c/pdb
• Related: 2ZGV 3C39 3C3A 3C3B
• Descriptor: Phosphoglycerate kinase 1, MAGNESIUM ION, 3-PHOSPHOGLYCERIC ACID, ... (5 entities in total)
• Functional Keywords: protein-nucleotide complex, l-enantiomer of cdp, kinase, acetylation, atp-binding, cytoplasm, disease mutation, glycolysis, hereditary hemolytic anemia, nucleotide-binding, phosphoprotein, polymorphism, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P00558
• Total number of polymer chains: 2
• Total formula weight: 90709.38

Authors

Arold, S.T.,Gondeau, C.,Lionne, C.,Chaloin, L. (deposition date: 2008-01-28, release date: 2008-07-01, Last modification date: 2024-10-16)

Primary citation

Gondeau, C.,Chaloin, L.,Lallemand, P.,Roy, B.,Perigaud, C.,Barman, T.,Varga, A.,Vas, M.,Lionne, C.,Arold, S.T.
Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase
Nucleic Acids Res., 36:3620-3629, 2008

PubMed Abstract: Non-natural L-nucleoside analogues are increasingly used as therapeutic agents to treat cancer and viral infections. To be active, L-nucleosides need to be phosphorylated to their respective triphosphate metabolites. This stepwise phosphorylation relies on human enzymes capable of processing L-nucleoside enantiomers. We used crystallographic analysis to reveal the molecular basis for the low enantioselectivity and the broad specificity of human 3-phosphoglycerate kinase (hPGK), an enzyme responsible for the last step of phosphorylation of many nucleotide derivatives. Based on structures of hPGK in the absence of nucleotides, and bound to L and d forms of MgADP and MgCDP, we show that a non-specific hydrophobic clamp to the nucleotide base, as well as a water-filled cavity behind it, allows high flexibility in the interaction between PGK and the bases. This, combined with the dispensability of hydrogen bonds to the sugar moiety, and ionic interactions with the phosphate groups, results in the positioning of different nucleotides so to expose their diphosphate group in a position competent for catalysis. Since the third phosphorylation step is often rate limiting, our results are expected to alleviate in silico tailoring of L-type prodrugs to assure their efficient metabolic processing.

PubMed: 18463139
DOI: 10.1093/nar/gkn212

Experimental method

X-RAY DIFFRACTION (2.4 Å)