8cxx: Difference between revisions
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The | ==CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor MC4683 (Compound 165)== | ||
<StructureSection load='8cxx' size='340' side='right'caption='[[8cxx]], [[Resolution|resolution]] 2.34Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8cxx]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridioides_difficile Clostridioides difficile] and [https://en.wikipedia.org/wiki/Clostridioides_difficile_630 Clostridioides difficile 630]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CXX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CXX FirstGlance]. <br> | |||
</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=T9I:N-[(1R)-2,3-dihydro-1H-inden-1-yl]adenosine'>T9I</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=8cxx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cxx OCA], [https://pdbe.org/8cxx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cxx RCSB], [https://www.ebi.ac.uk/pdbsum/8cxx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cxx ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q183J3_CLOD6 Q183J3_CLOD6] | |||
<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 8cxx" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Clostridioides difficile]] | |||
[[Category: Clostridioides difficile 630]] | |||
[[Category: Large Structures]] | |||
[[Category: Cheng X]] | |||
[[Category: Horton JR]] | |||
[[Category: Zhou J]] | |||
Revision as of 10:41, 11 January 2023
CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor MC4683 (Compound 165)CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor MC4683 (Compound 165)
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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