4E9U

Crystal structure of dehydrosqualene synthase (Crtm) from S. aureus complexed with a thiocyanate inhibitor

Summary for 4E9U

• Entry DOI: 10.2210/pdb4e9u/pdb
• Related: 4E9Z 4EA0 4EA1 4EA2
• Descriptor: Dehydrosqualene synthase, 2-(4-phenoxyphenoxy)ethyl thiocyanate, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: prenyl transferase, thiocyanate inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 34656.67

Authors

Lin, F.-Y.,Axelson, J.,Liu, Y.-L.,Zhnag, Y.,Oldfield, E. (deposition date: 2012-03-21, release date: 2012-04-25, Last modification date: 2024-02-28)

Primary citation

Lin, F.Y.,Liu, Y.L.,Li, K.,Cao, R.,Zhu, W.,Axelson, J.,Pang, R.,Oldfield, E.
Head-to-Head Prenyl Tranferases: Anti-Infective Drug Targets.
J.Med.Chem., 55:4367-4372, 2012

PubMed Abstract: We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine's cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design.

PubMed: 22486710
DOI: 10.1021/jm300208p

Experimental method

X-RAY DIFFRACTION (2.1 Å)