7nag

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==Crystal structure of the TIR domain from human SARM1 in complex with 1AD==
==Crystal structure of the TIR domain from human SARM1 in complex with 1AD==
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<StructureSection load='7nag' size='340' side='right'caption='[[7nag]]' scene=''>
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<StructureSection load='7nag' size='340' side='right'caption='[[7nag]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NAG FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7nag]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NAG FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nag OCA], [https://pdbe.org/7nag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nag RCSB], [https://www.ebi.ac.uk/pdbsum/7nag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nag ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1QD:[[(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})-5-(5-iodanylisoquinolin-2-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl+hydrogen+phosphate'>1QD</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nag OCA], [https://pdbe.org/7nag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nag RCSB], [https://www.ebi.ac.uk/pdbsum/7nag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nag ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[https://www.uniprot.org/uniprot/SARM1_HUMAN SARM1_HUMAN]] Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.<ref>PMID:15123841</ref> <ref>PMID:16964262</ref> <ref>PMID:16985498</ref> <ref>PMID:20306472</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD(+)) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD(+) mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.
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Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.,Shi Y, Kerry PS, Nanson JD, Bosanac T, Sasaki Y, Krauss R, Saikot FK, Adams SE, Mosaiab T, Masic V, Mao X, Rose F, Vasquez E, Furrer M, Cunnea K, Brearley A, Gu W, Luo Z, Brillault L, Landsberg MJ, Di Antonio A, Kobe B, Milbrandt J, Hughes RO, Ve T Mol Cell. 2022 Mar 18. pii: S1097-2765(22)00216-7. doi:, 10.1016/j.molcel.2022.03.007. PMID:35334231<ref>PMID:35334231</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7nag" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Bosanac T]]
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[[Category: Bosanac, T]]
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[[Category: Hughes RO]]
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[[Category: Hughes, R O]]
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[[Category: Shi Y]]
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[[Category: Shi, Y]]
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[[Category: Ve T]]
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[[Category: Ve, T]]
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[[Category: Axon degeneration]]
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[[Category: Hydrolase]]
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[[Category: Nadase]]

Revision as of 10:34, 6 April 2022

Crystal structure of the TIR domain from human SARM1 in complex with 1AD

PDB ID 7nag

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