7bum: Difference between revisions
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==mcGAS bound with pGpA== | |||
<StructureSection load='7bum' size='340' side='right'caption='[[7bum]], [[Resolution|resolution]] 3.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BUM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BUM FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.047Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5GP:GUANOSINE-5-MONOPHOSPHATE'>5GP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=7bum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bum OCA], [https://pdbe.org/7bum PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bum RCSB], [https://www.ebi.ac.uk/pdbsum/7bum PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bum ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
DNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg(2+) as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn(2+) potentiates cGAS activation, but the underlying mechanism remains unclear. Here, we report that Mn(2+) directly activates cGAS. Structural analysis reveals that Mn(2+)-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique eta1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn(2+)-activated cGAS, the linear intermediates pppGpG and pGpA take an inverted orientation in the active pocket, suggesting a noncanonical but accelerated cGAMP cyclization without substrate flip-over. Moreover, unlike the octahedral coordination around Mg(2+), the two catalytic Mn(2+) are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn(2+) as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis. | |||
Mn(2+) Directly Activates cGAS and Structural Analysis Suggests Mn(2+) Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.,Zhao Z, Ma Z, Wang B, Guan Y, Su XD, Jiang Z Cell Rep. 2020 Aug 18;32(7):108053. doi: 10.1016/j.celrep.2020.108053. PMID:32814054<ref>PMID:32814054</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7bum" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Su XD]] | |||
[[Category: Wang B]] | |||
Latest revision as of 22:30, 29 May 2024
mcGAS bound with pGpAmcGAS bound with pGpA
Structural highlights
Publication Abstract from PubMedDNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg(2+) as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn(2+) potentiates cGAS activation, but the underlying mechanism remains unclear. Here, we report that Mn(2+) directly activates cGAS. Structural analysis reveals that Mn(2+)-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique eta1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn(2+)-activated cGAS, the linear intermediates pppGpG and pGpA take an inverted orientation in the active pocket, suggesting a noncanonical but accelerated cGAMP cyclization without substrate flip-over. Moreover, unlike the octahedral coordination around Mg(2+), the two catalytic Mn(2+) are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn(2+) as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis. Mn(2+) Directly Activates cGAS and Structural Analysis Suggests Mn(2+) Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.,Zhao Z, Ma Z, Wang B, Guan Y, Su XD, Jiang Z Cell Rep. 2020 Aug 18;32(7):108053. doi: 10.1016/j.celrep.2020.108053. PMID:32814054[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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