7T0B
Cryptococcus neoformans protein farnesyltransferase in complex with FPP and inhibitor 2g
Summary for 7T0B
| Entry DOI | 10.2210/pdb7t0b/pdb |
| Related | 7T08 7T09 7T0A 7T0C 7T0D 7T0E |
| Descriptor | Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Protein farnesyltransferase subunit beta, 1,2-ETHANEDIOL, ... (8 entities in total) |
| Functional Keywords | inhibitor, protein prenylyltransferase, antifungal, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Cryptococcus neoformans var. grubii H99 More |
| Total number of polymer chains | 2 |
| Total formula weight | 103915.28 |
| Authors | Wang, Y.,Shi, Y.,Beese, L.S. (deposition date: 2021-11-29, release date: 2022-11-09, Last modification date: 2023-10-18) |
| Primary citation | Wang, Y.,Xu, F.,Nichols, C.B.,Shi, Y.,Hellinga, H.W.,Alspaugh, J.A.,Distefano, M.D.,Beese, L.S. Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase. J.Med.Chem., 65:13753-13770, 2022 Cited by PubMed Abstract: Infections 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 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 levels of enzyme and farnesyl substrate. We elucidated how chemical modifications of the antifungals encode desired inhibitor conformation and concomitant inhibitory mechanism. PubMed: 36218371DOI: 10.1021/acs.jmedchem.2c00902 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.026 Å) |
Structure validation
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