Chandra Vikas, Wu Dalei, Li Sheng, Potluri Nalini, Kim Youngchang, Rastinejad Fraydoon
Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, 32827, USA.
Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Qingdao, Shandong, 266237, China.
Nat Commun. 2017 Oct 11;8(1):868. doi: 10.1038/s41467-017-00981-y.
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARβ ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.Nuclear receptors (NR) are multidomain proteins, which makes their crystallization challenging. Here the authors present the crystal structure of the retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, which shows that NR quaternary architectures are variable.
评估多结构域核受体（NR）多肽中的物理连接和变构通讯一直具有挑战性，因为几乎没有晶体结构可用于展示其整体结构组织。在此，我们报告了通过晶体学、氢-氘交换质谱、诱变和功能研究检测到的与DNA、配体和共激活剂肽结合的多结构域视黄酸受体β-视黄酸X受体α（RARβ-RXRα）异二聚体的四级结构。RARβ配体结合结构域（LBD）和DNA结合结构域（DBD）在物理上相互连接，以促进它们之间的变构信号传递。对迄今为止通过晶体学研究的所有多结构域NR进行直接比较，结果显示它们的四级结构存在显著差异，而非遵循严格规则的共同结构。RXR通过保持结构域松散组织而保持灵活性和适应性，而其异二聚体伙伴则利用其LBD上的一个表面斑块与DBD形成结构域-结构域相互作用。核受体（NR）是多结构域蛋白，这使得它们的结晶具有挑战性。在此，作者展示了与DNA、配体和共激活剂肽结合的视黄酸受体β-视黄酸X受体α（RARβ-RXRα）异二聚体的晶体结构，该结构表明NR的四级结构是可变的。
