SIN3–HDAC (histone deacetylases) complexes have important roles in facilitating local histone deacetylation to regulate chromatin accessibility and gene expression. Here, we present the cryo-EM structure of the budding yeast SIN3–HDAC complex Rpd3L at an average resolution of 2.6 Å. The structure reveals that two distinct arms (ARM1 and ARM2) hang on a T-shaped scaffold formed by two coiled-coil domains. In each arm, Sin3 interacts with different subunits to create a different environment for the histone deacetylase Rpd3. ARM1 is in the inhibited state with the active site of Rpd3 blocked, whereas ARM2 is in an open conformation with the active site of Rpd3 exposed to the exterior space. The observed asymmetric architecture of Rpd3L is different from those of available structures of other class I HDAC complexes. Our study reveals the organization mechanism of the SIN3–HDAC complex and provides insights into the interaction pattern by which it targets histone deacetylase to chromatin.

SIN3-HDAC（组蛋白脱乙酰酶）复合物在促进局部组蛋白脱乙酰化以调节染色质可及性和基因表达方面具有重要作用。在这里，我们展示了芽殖酵母 SIN3-HDAC 复合物 Rpd3L 的冷冻电镜结构，平均分辨率为 2.6 Å。该结构揭示了两个不同的臂（ARM1 和 ARM2）悬挂在由两个卷曲螺旋结构域形成的 T 形支架上。在每个臂中，Sin3 与不同的亚基相互作用，为组蛋白脱乙酰酶 Rpd3 创造不同的环境。ARM1处于抑制状态，Rpd3的活性位点被阻断，而ARM2处于开放构象，Rpd3的活性位点暴露于外部空间。观察到的 Rpd3L 的不对称结构与其他 I 类 HDAC 复合物的可用结构不同。我们的研究揭示了 SIN3-HDAC 复合物的组织机制，并深入了解其将组蛋白脱乙酰酶靶向染色质的相互作用模式。