View source for 7rfl


==CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor SGC0946==
<StructureSection load='7rfl' size='340' side='right'caption='[[7rfl]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rfl]] 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=7RFL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RFL 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]] 2.38&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AW2:5-BROMO-7-{5-[(3-{[(4-TERT-BUTYLPHENYL)CARBAMOYL]AMINO}PROPYL)(PROPAN-2-YL)AMINO]-5-DEOXY-BETA-D-RIBOFURANOSYL}-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE'>AW2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=7rfl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rfl OCA], [https://pdbe.org/7rfl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rfl RCSB], [https://www.ebi.ac.uk/pdbsum/7rfl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rfl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q183J3_CLOD6 Q183J3_CLOD6] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Epigenetically targeted therapeutic development, particularly for SAM-dependent methylations of DNA, mRNA and histones has been proceeding rapidly for cancer treatments over the past few years. However, this approach has barely begun to be exploited for developing new antibiotics, despite an overwhelming global need to counter antimicrobial resistance. Here, we explore whether SAM analogues, some of which are in (pre)clinical studies as inhibitors of human epigenetic enzymes, can also inhibit Clostridioides difficile-specific DNA adenine methyltransferase (CamA), a sporulation regulator present in all C. difficile genomes sequenced to date, but found in almost no other bacteria. We found that SGC0946 (an inhibitor of DOT1L), JNJ-64619178 (an inhibitor of PRMT5) and SGC8158 (an inhibitor of PRMT7) inhibit CamA enzymatic activity in vitro at low micromolar concentrations. Structural investigation of the ternary complexes of CamA-DNA in the presence of SGC0946 or SGC8158 revealed conformational rearrangements of the N-terminal arm, with no apparent disturbance of the active site. This N-terminal arm and its modulation of exchanges between SAM (the methyl donor) and SAH (the reaction product) during catalysis of methyl transfer are, to date, unique to CamA. Our work presents a substantial first step in generating potent and selective inhibitors of CamA that would serve in the near term as chemical probes to investigate the cellular mechanism(s) of CamA in controlling spore formation and colonization, and eventually as therapeutic antivirulence agents useful in treating C. difficile infection.

Repurposing epigenetic inhibitors to target the Clostridioides difficile-specific DNA adenine methyltransferase and sporulation regulator CamA.,Zhou J, Horton JR, Yu D, Ren R, Blumenthal RM, Zhang X, Cheng X Epigenetics. 2022 Sep;17(9):970-981. doi: 10.1080/15592294.2021.1976910. Epub, 2021 Sep 15. PMID:34523387<ref>PMID:34523387</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7rfl" style="background-color:#fffaf0;"></div>

==See Also==
*[[DNA methyltransferase 3D structures|DNA methyltransferase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Clostridioides difficile]]
[[Category: Clostridioides difficile 630]]
[[Category: Large Structures]]
[[Category: Cheng X]]
[[Category: Horton JR]]
[[Category: Zhou J]]