Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6

Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6–inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.

组蛋白去乙酰化酶6（histone deacetylase 6，HDAC6）抑制已成为治疗癌症、化疗诱导性周围神经病及神经退行性疾病的极具潜力的治疗策略。近期HDAC6的X射线晶体结构解析，使我们得以阐明其活性位点中调控结合亲和力与选择性的结构特征。本研究报道了5种HDAC6-抑制剂复合物的X射线晶体结构，这些结构阐明了抑制剂连接臂与帽状基团的关键分子特征，这些特征可促进并区分与HDAC6的结合。具体而言，芳香族与杂芳香族连接臂嵌套于由F583和F643构成的芳香裂隙中，而不同的芳香族连接臂可引导帽状基团朝向由L1环、L2环或二者之间区域所定义的浅口袋。本研究结果拓展了我们对HDAC6选择性抑制相关影响因素的认知，尤其是针对L2口袋区域可开展靶向干预的相互作用机制。