Structure of the Methanococcus jannaschii mevalonate kinase, a member of the GHMP kinase superfamily.
The mevalonate-dependent pathway is used by many organisms to synthesize isopentenyl pyrophosphate, the building block for the biosynthesis of many biologically important compounds, including farnesyl pyrophosphate, dolichol, and many sterols. Mevalonate kinase (MVK) catalyzes a critical phosphoryl transfer step, producing mevalonate 5'-phosphate. The crystal structure of thermostable MVK from Methanococcus jannaschii has been determined at 2.4 A, revealing an overall fold similar to the homoserine kinase from M. jannaschii. In addition, the enzyme shows structural similarity with mevalonate 5-diphosphate decarboxylase and domain IV of elongation factor G. The active site of MVK is in the cleft between its N- and C-terminal domains. Several structural motifs conserved among species, including a phosphate-binding loop, have been found in this cavity. Asp(155), an invariant residue among MVK sequences, is located close to the putative phosphate-binding site and has been assumed to play the catalytic role. Analysis of the MVK model in the context of the other members of the GHMP kinase family offers the opportunity to understand both the mechanism of these enzymes and the structural details that may lead to the design of novel drugs.
Yang
Dong
D
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128 and Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255.
Shipman
Lance W
LW
Roessner
Charles A
CA
Scott
A Ian
AI
Sacchettini
James C
JC
D000595:Amino Acid Sequence; D001665:Binding Sites; D003460:Crystallization; D005686:Galactokinase / Q000737:chemistry; D017017:Methanococcus / Q000201:enzymology*; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000737:chemistry; D017510:Protein Folding
D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; C021370:homoserine kinase; D005686:Galactokinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase