7T09

Cryptococcus neoformans protein farnesyltransferase in complex with FPP and inhibitor 2d

7T09 の概要

• エントリーDOI: 10.2210/pdb7t09/pdb
• 関連するPDBエントリー: 7T08 7T0A 7T0B 7T0C 7T0D 7T0E
• 分子名称: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Protein farnesyltransferase subunit beta, 1,2-ETHANEDIOL, ... (8 entities in total)
• 機能のキーワード: inhibitor, protein prenylyltransferase, antifungal, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Cryptococcus neoformans var. grubii H99; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 102308.53

構造登録者

Wang, Y.,Shi, Y.,Beese, L.S. (登録日: 2021-11-29, 公開日: 2022-11-09, 最終更新日: 2023-10-18)

主引用文献

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

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: 36218371
DOI: 10.1021/acs.jmedchem.2c00902

実験手法

X-RAY DIFFRACTION (1.984 Å)