9TZWSummary for 9TZW
| Entry DOI | 10.2210/pdb9tzw/pdb |
| EMDB information | 56477 |
| Descriptor | NAD(+) hydrolase SARM1, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-[4-[[4-(pyridin-2-ylcarbamoylamino)phenyl]methyl]pyridin-1-yl]oxolan-2-yl]methyl hydrogen phosphate (2 entities in total) |
| Functional Keywords | nad(+), hydrolase, sarm1, tir |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 67980.70 |
| Authors | |
| Primary citation | Lundback, T.,Chandrasekar, V.,Gu, C.,Ju, H.,McAdam, R.,Palomero, M.,Sader, K.,Peter, B.,Wissler, L.,Nevin, P.,Foster, E.,Jamier, T.,Manjappa, P.,Johansson, C.,Sandmark, J.,Ding, M.,Persson-Kry, A.,Mitra, S.,Munise Satir, T.,Bilican, B.,Messa, M.,Fraser, G.,Linley, J.,Plant, H.,Moore, R.,Seifert, T.,Lerche, M.,Raynochek, C.,Nilsson, E.,Majbour, N.,Lucey, R.,Maia de Oliveira, T.,Wang, Q.,Chessell, I.,Breccia, P.,Jarvis, R. The rise and fall of SARM1 base-exchange inhibitors. Commun Chem, 9:-, 2026 Cited by PubMed Abstract: The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades. PubMed: 42156967DOI: 10.1038/s42004-026-02074-8 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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