7DJT

Human SARM1 inhibitory state bounded with inhibitor dHNN

Summary for 7DJT

• Entry DOI: 10.2210/pdb7djt/pdb
• EMDB information: 30700
• Descriptor: NAD(+) hydrolase SARM1, O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)phenyl]pyridine-3,5-dicarboxylate (2 entities in total)
• Functional Keywords: nad(+) hydrolase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 616256.57

Authors

Cai, Y.,Zhang, H. (deposition date: 2020-11-21, release date: 2021-05-19, Last modification date: 2023-11-15)

Primary citation

Li, W.H.,Huang, K.,Cai, Y.,Wang, Q.W.,Zhu, W.J.,Hou, Y.N.,Wang, S.,Cao, S.,Zhao, Z.Y.,Xie, X.J.,Du, Y.,Lee, C.S.,Lee, H.C.,Zhang, H.,Zhao, Y.J.
Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.
Elife, 10:-, 2021

PubMed Abstract: SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

PubMed: 33944777
DOI: 10.7554/eLife.67381

Experimental method

ELECTRON MICROSCOPY (2.8 Å)