8cy2: Difference between revisions
New page: '''Unreleased structure''' The entry 8cy2 is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor APNEA (Compound 168)== | ||
<StructureSection load='8cy2' size='340' side='right'caption='[[8cy2]], [[Resolution|resolution]] 2.81Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8cy2]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridioides_difficile Clostridioides difficile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CY2 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]] 2.81Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=QA2:N-[2-(4-aminophenyl)ethyl]adenosine'>QA2</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=8cy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cy2 OCA], [https://pdbe.org/8cy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cy2 RCSB], [https://www.ebi.ac.uk/pdbsum/8cy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cy2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A031WG99_CLODI A0A031WG99_CLODI] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound 39 (IC(50) approximately 0.4 muM and K(D) approximately 0.2 muM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors. | |||
Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.,Zhou J, Horton JR, Menna M, Fiorentino F, Ren R, Yu D, Hajian T, Vedadi M, Mazzoccanti G, Ciogli A, Weinhold E, Huben M, Blumenthal RM, Zhang X, Mai A, Rotili D, Cheng X J Med Chem. 2022 Dec 29. doi: 10.1021/acs.jmedchem.2c01789. PMID:36581322<ref>PMID:36581322</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8cy2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Clostridioides difficile]] | |||
[[Category: Large Structures]] | |||
[[Category: Cheng X]] | |||
[[Category: Horton JR]] | |||
[[Category: Zhou J]] | |||
Latest revision as of 13:04, 25 October 2023
CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor APNEA (Compound 168)CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor APNEA (Compound 168)
Structural highlights
FunctionPublication Abstract from PubMedAntivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound 39 (IC(50) approximately 0.4 muM and K(D) approximately 0.2 muM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors. Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.,Zhou J, Horton JR, Menna M, Fiorentino F, Ren R, Yu D, Hajian T, Vedadi M, Mazzoccanti G, Ciogli A, Weinhold E, Huben M, Blumenthal RM, Zhang X, Mai A, Rotili D, Cheng X J Med Chem. 2022 Dec 29. doi: 10.1021/acs.jmedchem.2c01789. PMID:36581322[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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