EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural basis of fungal β-1,3-glucan synthase inhibition by caspofungin.
ジャーナル・号・ページ	Nature, Vol. 654, Issue 8118, Page 547-555, Year 2026
掲載日	2026年4月22日
著者	Zhenning Ren / Abhishek Chhetri / Chang Liu / ShuYu Offner / Kedar Sharma / Mario J Borgnia / Wonpil Im / Kenichi Yokoyama / Seok-Yong Lee /
PubMed 要旨	Invasive fungal infections pose life-threatening risks to the increasing population of immunocompromised patients. Treatment remains challenging due to limited antifungal drugs and increasing ...Invasive fungal infections pose life-threatening risks to the increasing population of immunocompromised patients. Treatment remains challenging due to limited antifungal drugs and increasing resistance. β-1,3-D-glucan synthase (GS), comprising the catalytic Fks1 and the regulatory small GTPase, Rho1 (refs. ), is the target of clinically important echinocandin antifungals. Despite recent studies, the mechanisms of GS catalysis, Rho1 regulation and echinocandin inhibition and resistance remain elusive. Here we present cryo-electron microscopy structures of native Saccharomyces cerevisiae Fks1 (ScFks1) solved under catalytically relevant conditions, revealing its interactions with the antifungal caspofungin (CFN), glucan product from the translocation channel and Rho1. CFN forms a ternary complex with nascent glucan and Fks1 at the membrane-protein interface, suggesting an unexpected role of CFN in stalling polymer translocation. Our echinocandin-resistant S643P structure suggests a resistance mechanism: the substitution destabilizes CFN and glucan binding through both allosteric structural perturbation and direct steric clash. Rho1 binding induces active site rearrangements essential for catalysis, including that of the 'latch loop' for donor substrate coordination. Furthermore, we identify YMR295C as an auxiliary subunit. These findings elucidate the mechanisms of GS-mediated glucan synthesis and its inhibition and resistance by echinocandins, laying the groundwork for rational antifungal design.
リンク	Nature / PubMed:42020744 / PubMed Central
手法	EM (単粒子)
解像度	2.69 - 3.5 Å
構造データ	71550 9pe1 EMDB-71550, PDB-9pe1: Structure of beta-1,3-glucan synthase in complex with caspofungin, Rho1 and long glucan 手法: EM (単粒子) / 解像度: 3.09 Å 71551 9pe2 EMDB-71551, PDB-9pe2: Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) in complex with short glucan 手法: EM (単粒子) / 解像度: 3.07 Å 71552 9pe3 EMDB-71552, PDB-9pe3: Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) at the catalytically relevant ground state 手法: EM (単粒子) / 解像度: 3.26 Å 71553 9pe4 EMDB-71553, PDB-9pe4: Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) at the catalytically less relevant L2 state 手法: EM (単粒子) / 解像度: 2.69 Å 71554 9pe5 EMDB-71554, PDB-9pe5: Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) at the catalytically less relevant L1 state 手法: EM (単粒子) / 解像度: 2.8 Å 74746 9ztc EMDB-74746, PDB-9ztc: Beta-1,3-glucan synthase Fks1 S643P from Saccharomyces Cerevisiae 手法: EM (単粒子) / 解像度: 3.5 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose ChemComp-Y01: CHOLESTEROL HEMISUCCINATE ChemComp-3PE: 1,2-Distearoyl-sn-glycerophosphoethanolamine / リン脂質YM ChemComp-UDP: URIDINE-5'-DIPHOSPHATE / UDPYM ChemComp-GSP: 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE PDB 未公開エントリ PDB-1chr: Unknown entry ChemComp-HOH: WATER ChemComp-LMN: Lauryl Maltose Neopentyl Glycol / 可溶化剤*YM
由来	saccharomyces cerevisiae (パン酵母) synthetic construct (人工物)
キーワード	MEMBRANE PROTEIN / Enzyme / glucan synthesis