View source for 7seb


==Crystal structure of human Fibrillarin in complex with compound 2 from single soak==
<StructureSection load='7seb' size='340' side='right'caption='[[7seb]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7seb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SEB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SEB 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]] 1.81&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8XF:6-(trifluoromethyl)pyrimidin-4-amine'>8XF</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</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=7seb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7seb OCA], [https://pdbe.org/7seb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7seb RCSB], [https://www.ebi.ac.uk/pdbsum/7seb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7seb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FBRL_HUMAN FBRL_HUMAN] Involved in pre-rRNA processing. Utilizes the methyl donor S-adenosyl-L-methionine to catalyze the site-specific 2'-hydroxyl methylation of ribose moieties in pre-ribosomal RNA. Site specificity is provided by a guide RNA that base pairs with the substrate. Methylation occurs at a characteristic distance from the sequence involved in base pairing with the guide RNA.
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== Publication Abstract from PubMed ==
Fibrillarin (FBL) is an essential and evolutionarily highly conserved S-adenosyl methionine (SAM) dependent methyltransferase. It is the catalytic component of a multiprotein complex that facilitates 2'-O-methylation of ribosomal RNAs (rRNAs), a modification essential for accurate and efficient protein synthesis in eukaryotic cells. It was recently established that human FBL (hFBL) is critical for Nipah, Hendra, and respiratory syncytial virus infections. In addition, overexpression of hFBL contributes towards tumorgenesis and is associated with poor survival in patients with breast cancer, suggesting that hFBL is a potential target for the development of both antiviral and anticancer drugs. An attractive strategy to target cofactor-dependent enzymes is the selective inhibition of cofactor binding, which has been successful for the development of inhibitors against several protein methyltransferases including PRMT5, DOT1L, and EZH2. In this work, we solved crystal structures of the methyltransferase domain of hFBL in apo form and in complex with the cofactor SAM. Screening of a fluorinated fragment library, via X-ray crystallography and 19F NMR spectroscopy, yielded seven hit compounds that competed with cofactor binding, two of which resulted in co-crystal structures. One of these structures revealed unexpected conformational variability in the cofactor binding site, which allows it to accommodate a compound significantly different from SAM. Our structural data provide critical information for the design of selective cofactor competitive inhibitors targeting hFBL, and preliminary elaboration of hit compounds has led to additional cofactor site binders.

Discovery of Cofactor Competitive Inhibitors against the Human Methyltransferase Fibrillarin.,Shi Y, El-Deeb IM, Masic V, Hartley-Tassell L, Maggioni A, Itzstein MV, Ve T Pharmaceuticals (Basel). 2021 Dec 24;15(1). pii: ph15010026. doi:, 10.3390/ph15010026. PMID:35056083<ref>PMID:35056083</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7seb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: El-Deeb IM]]
[[Category: Hartley-Tassell L]]
[[Category: Maggioni A]]
[[Category: Masic V]]
[[Category: Shi Y]]
[[Category: Ve T]]
[[Category: Von Itzstein M]]