7JLR

Crystal structure of Bacillus subtilis UppS in complex with JPD447

Summary for 7JLR

• Entry DOI: 10.2210/pdb7jlr/pdb
• Related: 7JLI
• Descriptor: Isoprenyl transferase, 7-(azepan-1-yl)-5-ethyl-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (3 entities in total)
• Functional Keywords: undecaprenyl, cis-prenyltransferase, carrier lipid, jpd447, transferase
• Biological source: Bacillus subtilis
• Total number of polymer chains: 1
• Total formula weight: 30152.54

Authors

Workman, S.D.,Strynadka, N.C.J. (deposition date: 2020-07-30, release date: 2021-08-04, Last modification date: 2023-10-18)

Primary citation

Workman, S.D.,Day, J.,Farha, M.A.,El Zahed, S.S.,Bon, C.,Brown, E.D.,Organ, M.G.,Strynadka, N.C.J.
Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria.
J.Med.Chem., 64:13540-13550, 2021

PubMed Abstract: The polyprenyl lipid undecaprenyl phosphate (CP) is the universal carrier lipid for the biosynthesis of bacterial cell wall polymers. CP is synthesized in its pyrophosphate form by undecaprenyl pyrophosphate synthase (UppS), an essential -prenyltransferase that is an attractive target for antibiotic development. We previously identified a compound (MAC-0547630) that showed promise as a novel class of inhibitor and an ability to potentiate β-lactam antibiotics. Here, we provide a structural model for MAC-0547630's inhibition of UppS and a structural rationale for its enhanced effect on UppS from . We also describe the synthesis of a MAC-0547630 derivative (JPD447), show that it too can potentiate β-lactam antibiotics, and provide a structural rationale for its improved potentiation. Finally, we present an improved structural model of clomiphene's inhibition of UppS. Taken together, our data provide a foundation for structure-guided drug design of more potent UppS inhibitors in the future.

PubMed: 34473495
DOI: 10.1021/acs.jmedchem.1c00941

Experimental method

X-RAY DIFFRACTION (2.2 Å)