PDBsum entry 3c3c

Transferase

PDB id: 3c3c

Contents

Protein chain

403 a.a. *

Ligands

3PG ×2

CDP

Metals

_MG

Waters ×175

* Residue conservation analysis

PDB id:

3c3c

Name:

Transferase

Title:

Crystal structure of human phosphoglycerate kinase bound to 3- phosphoglycerate and l-cdp

Structure:

Phosphoglycerate kinase 1. Chain: a, b. Synonym: 3-phosphoglycerate kinase, primer recognition protein 2, prp 2, cell migration-inducing gene 10 protein. Engineered: yes

Source:

Homo sapiens. Human. Gene: pgk1. Expressed in: escherichia coli.

Resolution:

2.40Å R-factor: 0.196 R-free: 0.281

Authors:

S.T.Arold,C.Gondeau,C.Lionne,L.Chaloin

Key ref:

C.Gondeau et al. (2008). Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase. Nucleic Acids Res, 36, 3620-3629. PubMed id: 18463139

Date:

28-Jan-08 Release date: 01-Jul-08

Protein chains

P00558  (PGK1_HUMAN) -  Phosphoglycerate kinase 1 from Homo sapiens

Seq: 417 a.a.

Struc: 403 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.2.3 - phosphoglycerate kinase.
• Pathway: Calvin Cycle (carbon fixation stages)
• Reaction: (2R)-3-phosphoglycerate + ATP = (2R)-3-phospho-glyceroyl phosphate + ADP

(2R)-3-phosphoglycerate + ATP = (2R)-3-phospho-glyceroyl phosphate + ADP (Bound ligand (Het Group name = CDP) matches with 85.71% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

Nucleic Acids Res 36:3620-3629 (2008)

PubMed id: 18463139

Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase.

C.Gondeau, L.Chaloin, P.Lallemand, B.Roy, C.Périgaud, T.Barman, A.Varga, M.Vas, C.Lionne, S.T.Arold.

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.