8e9e
Rat protein farnesyltransferase in complex with FPP and inhibitor 2f
Structural highlights
FunctionFNTA_RAT Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity). Publication Abstract from PubMedInfections by fungal pathogens are difficult to treat due to a paucity of antifungals and emerging resistances. Next-generation antifungals therefore are needed urgently. We have developed compounds that prevent farnesylation of Cryptoccoccus neoformans Ras protein by inhibiting protein farnesyltransferase with 3-4 nanomolar affinities. Farnesylation directs Ras to the cell membrane and is required for infectivity of this lethal pathogenic fungus. Our high-affinity compounds inhibit fungal growth with 3-6 micromolar minimum inhibitory concentrations (MICs), 4- to 8-fold better than Fluconazole, an antifungal commonly used in the clinic. Compounds bound with distinct inhibition mechanisms at two alternative, partially overlapping binding sites, accessed via different inhibitor conformations. We showed that antifungal potency depends critically on the selected inhibition mechanism because this determines the efficacy of an inhibitor at low in vivo levels of enzyme and farnesyl substrate. We elucidated how chemical modifications of the antifungals encode desired inhibitor conformation and concomitant inhibitory mechanism. Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase.,Wang Y, Xu F, Nichols CB, Shi Y, Hellinga HW, Alspaugh JA, Distefano MD, Beese LS J Med Chem. 2022 Oct 11. doi: 10.1021/acs.jmedchem.2c00902. PMID:36218371[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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