Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase

Dimitrios Gritzalis; Jaeok Park; Wei Chiu; Hyungjun Cho; Yih-Shyan Lin; Joris W De Schutter; Cyrus M Lacbay; Michal Zielinski; Albert M Berghuis; Youla S Tsantrizos

doi:10.1016/j.bmcl.2014.12.089

Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase

Bioorg Med Chem Lett. 2015 Mar 1;25(5):1117-23. doi: 10.1016/j.bmcl.2014.12.089. Epub 2015 Jan 13.

Affiliations

¹ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
² Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
³ Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Department of Microbiology and Immunology, McGill University, 3775 Rue University, Montreal, QC H3A 2B4, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promenade Sir William Osler, Montréal, QC H3G 0B1, Canada.
⁴ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promenade Sir William Osler, Montréal, QC H3G 0B1, Canada. Electronic address: youla.tsantrizos@mcgill.ca.

PMID: 25630225
DOI: 10.1016/j.bmcl.2014.12.089

Abstract

In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg(2+) ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.

Keywords: Allosteric inhibitors; Bisphosphonates; Human FPPS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site
Catalytic Domain
Diphosphonates / chemistry
Diphosphonates / metabolism*
Geranyltranstransferase / chemistry*
Geranyltranstransferase / metabolism*
Humans
Ligands
Magnesium / metabolism
Molecular Docking Simulation
Protein Binding

Substances

Diphosphonates
Ligands
Geranyltranstransferase
Magnesium

Grants and funding

Canadian Institutes of Health Research/Canada