6K0R
Ruvbl1-Ruvbl2 with truncated domain II in complex with phosphorylated Cordycepin
Summary for 6K0R
Entry DOI | 10.2210/pdb6k0r/pdb |
Descriptor | RuvB-like 1,RuvB-like 1, RuvB-like 2,RuvB-like 2, ADENOSINE-5'-DIPHOSPHATE, ... (8 entities in total) |
Functional Keywords | atpase, cordycepin, circadian clock protein |
Biological source | Homo sapiens (Human) More |
Total number of polymer chains | 12 |
Total formula weight | 479665.67 |
Authors | |
Primary citation | Ju, D.,Zhang, W.,Yan, J.,Zhao, H.,Li, W.,Wang, J.,Liao, M.,Xu, Z.,Wang, Z.,Zhou, G.,Mei, L.,Hou, N.,Ying, S.,Cai, T.,Chen, S.,Xie, X.,Lai, L.,Tang, C.,Park, N.,Takahashi, J.S.,Huang, N.,Qi, X.,Zhang, E.E. Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals. Sci Transl Med, 12:-, 2020 Cited by PubMed Abstract: Transcriptional regulation lies at the core of the circadian clockwork, but how the clock-related transcription machinery controls the circadian phase is not understood. Here, we show both in human cells and in mice that RuvB-like ATPase 2 (RUVBL2) interacts with other known clock proteins on chromatin to regulate the circadian phase. Pharmacological perturbation of RUVBL2 with the adenosine analog compound cordycepin resulted in a rapid-onset 12-hour clock phase-shift phenotype at human cell, mouse tissue, and whole-animal live imaging levels. Using simple peripheral injection treatment, we found that cordycepin penetrated the blood-brain barrier and caused rapid entrainment of the circadian phase, facilitating reduced duration of recovery in a mouse jet-lag model. We solved a crystal structure for human RUVBL2 in complex with a physiological metabolite of cordycepin, and biochemical assays showed that cordycepin treatment caused disassembly of an interaction between RUVBL2 and the core clock component BMAL1. Moreover, we showed with spike-in ChIP-seq analysis and binding assays that cordycepin treatment caused disassembly of the circadian super-complex, which normally resides at E-box chromatin loci such as , , and Mathematical modeling supported that the observed type 0 phase shifts resulted from derepression of E-box clock gene transcription. PubMed: 32376767DOI: 10.1126/scitranslmed.aba0769 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.502 Å) |
Structure validation
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