2ZCO

Crystal structure of the C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus

Summary for 2ZCO

• Entry DOI: 10.2210/pdb2zco/pdb
• Related: 2ZCP 2ZCQ 2ZCR 2ZCS
• Descriptor: Dehydrosqualene synthase (2 entities in total)
• Functional Keywords: crtm, carotenoid biosynthesis, staphyloxanthin biosynthesis, transferase, head-to-head condensation
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 34787.50

Authors

Liu, C.I.,Jeng, W.Y.,Wang, A.H.,Oldfield, E. (deposition date: 2007-11-11, release date: 2008-03-11, Last modification date: 2024-03-13)

Primary citation

Liu, C.I.,Liu, G.Y.,Song, Y.,Yin, F.,Hensler, M.E.,Jeng, W.Y.,Nizet, V.,Wang, A.H.,Oldfield, E.
A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence.
Science, 319:1391-1394, 2008

PubMed Abstract: Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration approximately 100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus.

PubMed: 18276850
DOI: 10.1126/science.1153018

Experimental method

X-RAY DIFFRACTION (1.58 Å)