5V2L

Mevalonate diphosphate mediated ATP binding mechanism of the mevalonate diphosphate decarboxylase from Enterococcus faecalis

Summary for 5V2L

• Entry DOI: 10.2210/pdb5v2l/pdb
• Related: 5V2M
• Descriptor: Mevalonate diphosphate decarboxylase, ADENOSINE-5'-TRIPHOSPHATE, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: the mevalonate pathway, vancomycin resistant enterococci, enzyme kinetics, isothermal titration calorimetry., lyase
• Biological source: Enterococcus faecalis V583
• Total number of polymer chains: 1
• Total formula weight: 37304.71

Authors

Stauffacher, C.V.,Chen, C.-L. (deposition date: 2017-03-05, release date: 2017-10-18, Last modification date: 2023-10-04)

Primary citation

Chen, C.L.,Mermoud, J.C.,Paul, L.N.,Steussy, C.N.,Stauffacher, C.V.
Mevalonate 5-diphosphate mediates ATP binding to the mevalonate diphosphate decarboxylase from the bacterial pathogen Enterococcus faecalis.
J. Biol. Chem., 292:21340-21351, 2017

PubMed Abstract: The mevalonate pathway produces isopentenyl diphosphate (IPP), a building block for polyisoprenoid synthesis, and is a crucial pathway for growth of the human bacterial pathogen The final enzyme in this pathway, mevalonate diphosphate decarboxylase (MDD), acts on mevalonate diphosphate (MVAPP) to produce IPP while consuming ATP. This essential enzyme has been suggested as a therapeutic target for the treatment of drug-resistant bacterial infections. Here, we report functional and structural studies on the mevalonate diphosphate decarboxylase from (MDD). The MDD crystal structure in complex with ATP (MDD-ATP) revealed that the phosphate-binding loop (amino acids 97-105) is not involved in ATP binding and that the phosphate tail of ATP in this structure is in an outward-facing position pointing away from the active site. This suggested that binding of MDD to MVAPP is necessary to guide ATP into a catalytically favorable position. Enzymology experiments show that the MDD performs a sequential ordered bi-substrate reaction with MVAPP as the first substrate, consistent with the isothermal titration calorimetry (ITC) experiments. On the basis of ITC results, we propose that this initial prerequisite binding of MVAPP enhances ATP binding. In summary, our findings reveal a substrate-induced substrate-binding event that occurs during the MDD-catalyzed reaction. The disengagement of the phosphate-binding loop concomitant with the alternative ATP-binding configuration may provide the structural basis for antimicrobial design against these pathogenic enterococci.

PubMed: 29025876
DOI: 10.1074/jbc.M117.802223

Experimental method

X-RAY DIFFRACTION (2.1 Å)