7lz3: Difference between revisions
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==Computational design of constitutively active cGAS== | ==Computational design of constitutively active cGAS== | ||
<StructureSection load='7lz3' size='340' side='right'caption='[[7lz3]]' scene=''> | <StructureSection load='7lz3' size='340' side='right'caption='[[7lz3]], [[Resolution|resolution]] 2.18Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LZ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LZ3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lz3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LZ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LZ3 FirstGlance]. <br> | ||
</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=7lz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lz3 OCA], [https://pdbe.org/7lz3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lz3 RCSB], [https://www.ebi.ac.uk/pdbsum/7lz3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lz3 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7lz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lz3 OCA], [https://pdbe.org/7lz3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lz3 RCSB], [https://www.ebi.ac.uk/pdbsum/7lz3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lz3 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor critical for the innate immune response to intracellular pathogens, DNA damage, tumorigenesis and senescence. Binding to double-stranded DNA (dsDNA) induces conformational changes in cGAS that activate the enzyme to produce 2'-3' cyclic GMP-AMP (cGAMP), a second messenger that initiates a potent interferon (IFN) response through its receptor, STING. Here, we combined two-state computational design with informatics-guided design to create constitutively active, dsDNA ligand-independent cGAS (CA-cGAS). We identified CA-cGAS mutants with IFN-stimulating activity approaching that of dsDNA-stimulated wild-type cGAS. DNA-independent adoption of the active conformation was directly confirmed by X-ray crystallography. In vivo expression of CA-cGAS in tumor cells resulted in STING-dependent tumor regression, demonstrating that the designed proteins have therapeutically relevant biological activity. Our work provides a general framework for stabilizing active conformations of enzymes and provides CA-cGAS variants that could be useful as genetically encoded adjuvants and tools for understanding inflammatory diseases. | |||
Computational design of constitutively active cGAS.,Dowling QM, Volkman HE, Gray EE, Ovchinnikov S, Cambier S, Bera AK, Sankaran B, Johnson MR, Bick MJ, Kang A, Stetson DB, King NP Nat Struct Mol Biol. 2023 Jan;30(1):72-80. doi: 10.1038/s41594-022-00862-z. Epub , 2023 Jan 2. PMID:36593311<ref>PMID:36593311</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lz3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Synthetic construct]] | |||
[[Category: Bera AK]] | [[Category: Bera AK]] | ||
[[Category: Bick M]] | [[Category: Bick M]] | ||
Latest revision as of 13:38, 22 May 2024
Computational design of constitutively active cGASComputational design of constitutively active cGAS
Structural highlights
Publication Abstract from PubMedCyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor critical for the innate immune response to intracellular pathogens, DNA damage, tumorigenesis and senescence. Binding to double-stranded DNA (dsDNA) induces conformational changes in cGAS that activate the enzyme to produce 2'-3' cyclic GMP-AMP (cGAMP), a second messenger that initiates a potent interferon (IFN) response through its receptor, STING. Here, we combined two-state computational design with informatics-guided design to create constitutively active, dsDNA ligand-independent cGAS (CA-cGAS). We identified CA-cGAS mutants with IFN-stimulating activity approaching that of dsDNA-stimulated wild-type cGAS. DNA-independent adoption of the active conformation was directly confirmed by X-ray crystallography. In vivo expression of CA-cGAS in tumor cells resulted in STING-dependent tumor regression, demonstrating that the designed proteins have therapeutically relevant biological activity. Our work provides a general framework for stabilizing active conformations of enzymes and provides CA-cGAS variants that could be useful as genetically encoded adjuvants and tools for understanding inflammatory diseases. Computational design of constitutively active cGAS.,Dowling QM, Volkman HE, Gray EE, Ovchinnikov S, Cambier S, Bera AK, Sankaran B, Johnson MR, Bick MJ, Kang A, Stetson DB, King NP Nat Struct Mol Biol. 2023 Jan;30(1):72-80. doi: 10.1038/s41594-022-00862-z. Epub , 2023 Jan 2. PMID:36593311[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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