The SAGA complex is a regulatory hub involved in gene regulation, chromatin modification, DNA damage repair and signaling. While structures of yeast SAGA (ySAGA) have been reported, there are noteworthy functional and compositional differences for this complex in metazoans. Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA) and show how the arrangement of distinct structural elements results in a globally divergent organization from that of yeast, with a different interface tethering the core module to the TRRAP subunit, resulting in a dramatically altered geometry of functional elements and with the integration of a metazoan-specific splicing module. Our hSAGA structure reveals the presence of an inositol hexakisphosphate (InsP₆) binding site in TRRAP and an unusual property of its pseudo-(Ψ)PIKK. Finally, we map human disease mutations, thus providing the needed framework for structure-guided drug design of this important therapeutic target for human developmental diseases and cancer.

SAGA 复合体是参与基因调控、染色质修饰、DNA 损伤修复和信号传导的调控中心。虽然酵母 SAGA (ySAGA) 的结构已被报道，但这种复合体在后生动物中存在值得注意的功能和组成差异。在这里，我们展示了人类 SAGA (hSAGA) 的低温电子显微镜 (cryo-EM) 结构，并展示了不同结构元件的排列如何导致与酵母组织完全不同的组织，并通过不同的界面将核心模块束缚到TRRAP 亚基，导致功能元件的几何形状发生显着改变，并整合后生动物特异性剪接模块。我们的 hSAGA 结构揭示了TRRAP 中肌醇六磷酸 (InsP ₆ ) 结合位点的存在及其伪 (Ψ)PIKK 的不寻常特性。最后，我们绘制了人类疾病突变图谱，从而为人类发育疾病和癌症的这一重要治疗靶点的结构指导药物设计提供了所需的框架。