2WYA

CRYSTAL STRUCTURE OF HUMAN MITOCHONDRIAL 3-HYDROXY-3-METHYLGLUTARYL- COENZYME A SYNTHASE 2 (HMGCS2)

Replaces:  2V4W

Summary for 2WYA

• Entry DOI: 10.2210/pdb2wya/pdb
• Descriptor: HYDROXYMETHYLGLUTARYL-COA SYNTHASE, MITOCHONDRIAL, 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A, GLYCEROL, ... (4 entities in total)
• Functional Keywords: steroid biosynthesis, cholesterol biosynthesis, mitochondria, mitochondrion, phosphoprotein, melavonate pathway, sterol biosynthesis, thiolase, acetylation, transferase, lipid synthesis, transit peptide, disease mutation
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion: P54868
• Total number of polymer chains: 4
• Total formula weight: 208982.43

Authors

Yue, W.W.,Shafqat, N.,Savitsky, P.,Roos, A.K.,Cooper, C.,Murray, J.W.,von Delft, F.,Arrowsmith, C.,Wikstrom, M.,Edwards, A.,Bountra, C.,Oppermann, U. (deposition date: 2009-11-13, release date: 2009-11-24, Last modification date: 2024-11-20)

Primary citation

Shafqat, N.,Turnbull, A.,Zschocke, J.,Oppermann, U.,Yue, W.W.
Crystal Structures of Human Hmg-Coa Synthase Isoforms Provide Insights Into Inherited Ketogenesis Disorders and Inhibitor Design.
J.Mol.Biol., 398:497-, 2010

PubMed Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A (CoA) synthase (HMGCS) catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA. It is ubiquitous across the phylogenetic tree and is broadly classified into three classes. The prokaryotic isoform is essential in Gram-positive bacteria for isoprenoid synthesis via the mevalonate pathway. The eukaryotic cytosolic isoform also participates in the mevalonate pathway but its end product is cholesterol. Mammals also contain a mitochondrial isoform; its deficiency results in an inherited disorder of ketone body formation. Here, we report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. Our data represent the first structures solved for human HMGCS and the mitochondrial isoform, allowing for the first time structural comparison among the three isoforms. This serves as a starting point for the development of isoform-specific inhibitors that have potential cholesterol-reducing and antibiotic applications. In addition, missense mutations that cause mitochondrial HMGCS deficiency have been mapped onto the hHMGCS2 structure to rationalize the structural basis for the disease pathology.

PubMed: 20346956
DOI: 10.1016/J.JMB.2010.03.034

Experimental method

X-RAY DIFFRACTION (1.7 Å)