View source for 7lmw


==Receptor for Advanced Glycation End Products VC1 domain in complex with 3-(3-((4-(4-carboxyphenoxy)benzyl)oxy)phenyl)-1H-indole-2-carboxylic acid==
<StructureSection load='7lmw' size='340' side='right'caption='[[7lmw]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LMW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LMW 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=Y6P:7-methyl-3-(1~{H}-pyrazol-4-yl)-1~{H}-indole-2-carboxylic+acid'>Y6P</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=7lmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lmw OCA], [https://pdbe.org/7lmw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lmw RCSB], [https://www.ebi.ac.uk/pdbsum/7lmw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lmw ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Receptor for Advanced Glycation End products (RAGE) is a pattern recognition receptor that signals for inflammation via the NF-kappaB pathway. RAGE has been pursued as a potential target to suppress symptoms of diabetes and is of interest in a number of other diseases associated with chronic inflammation, such as inflammatory bowel disease and bronchopulmonary dysplasia. Screening and optimization have previously produced small molecules that inhibit the activity of RAGE in cell-based assays, but efforts to develop a therapeutically viable direct-binding RAGE inhibitor have yet to be successful. Here, we show that a fragment-based approach can be applied to discover fundamentally new types of RAGE inhibitors that specifically target the ligand-binding surface. A series of systematic assays of structural stability, solubility, and crystallization were performed to select constructs of the RAGE ligand-binding domain and optimize conditions for NMR-based screening and co-crystallization of RAGE with hit fragments. An NMR-based screen of a highly curated ~14 000-member fragment library produced 21 fragment leads. Of these, three were selected for elaboration based on structure-activity relationships generated through cycles of structural analysis by X-ray crystallography, structure-guided design principles, and synthetic chemistry. These results, combined with crystal structures of the first linked fragment compounds, demonstrate the applicability of the fragment-based approach to the discovery of RAGE inhibitors.

A fragment-based approach to discovery of Receptor for Advanced Glycation End products inhibitors.,Kozlyuk N, Gilston BA, Salay LE, Gogliotti RD, Christov PP, Kim K, Ovee M, Waterson AG, Chazin WJ Proteins. 2021 Jun 22. doi: 10.1002/prot.26162. PMID:34156100<ref>PMID:34156100</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lmw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Chazin WJ]]
[[Category: Christov PP]]
[[Category: Gilston BA]]
[[Category: Gogliotti RD]]
[[Category: Kim K]]
[[Category: Kozlyuk N]]
[[Category: Ovee M]]
[[Category: Salay LE]]
[[Category: Waterson AG]]