View source for 8fs2


==CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor 11b (YD907)==
<StructureSection load='8fs2' size='340' side='right'caption='[[8fs2]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fs2]] 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=8FS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FS2 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]] 2.59&#8491;</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=YB5:5-S-{3-[N-(cyclohexylmethyl)carbamimidamido]propyl}-N-(3-phenylpropyl)-5-thioadenosine'>YB5</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=8fs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fs2 OCA], [https://pdbe.org/8fs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fs2 RCSB], [https://www.ebi.ac.uk/pdbsum/8fs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fs2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A031WG99_CLODI A0A031WG99_CLODI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
S-Adenosyl-l-methionine (SAM) analogs are adaptable tools for studying and therapeutically inhibiting SAM-dependent methyltransferases (MTases). Some MTases play significant roles in host-pathogen interactions, one of which is Clostridioides difficile-specific DNA adenine MTase (CamA). CamA is needed for efficient sporulation and alters persistence in the colon. To discover potent and selective CamA inhibitors, we explored modifications of the solvent-exposed edge of the SAM adenosine moiety. Starting from the two parental compounds (6e and 7), we designed an adenosine analog (11a) carrying a 3-phenylpropyl moiety at the adenine N6-amino group, and a 3-(cyclohexylmethyl guanidine)-ethyl moiety at the sulfur atom off the ribose ring. Compound 11a (IC(50) = 0.15 muM) is 10x and 5x more potent against CamA than 6e and 7, respectively. The structure of the CamA-DNA-inhibitor complex revealed that 11a adopts a U-shaped conformation, with the two branches folded toward each other, and the aliphatic and aromatic rings at the two ends interacting with one another. 11a occupies the entire hydrophobic surface (apparently unique to CamA) next to the adenosine binding site. Our work presents a hybrid knowledge-based and fragment-based approach to generating CamA inhibitors that would be chemical agents to examine the mechanism(s) of action and therapeutic potentials of CamA in C. difficile infection.

Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile-Specific DNA Adenine Methyltransferase.,Zhou J, Deng Y, Iyamu ID, Horton JR, Yu D, Hajian T, Vedadi M, Rotili D, Mai A, Blumenthal RM, Zhang X, Huang R, Cheng X ACS Chem Biol. 2023 Apr 21;18(4):734-745. doi: 10.1021/acschembio.3c00035. Epub , 2023 Feb 22. PMID:37082867<ref>PMID:37082867</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8fs2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Clostridioides difficile]]
[[Category: Large Structures]]
[[Category: Cheng X]]
[[Category: Horton JR]]
[[Category: Zhou J]]