View source for 7lmr


==Structure of full-length human lambda-6A light chain JTO in complex with stabilizer 63 [4-methyl-3-(morpholinomethyl)-7-(2-phenylpropoxy)-2H-chromen-2-one]==
<StructureSection load='7lmr' size='340' side='right'caption='[[7lmr]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LMR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LMR 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]] 2.09&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9ZX:4-methyl-3-(morpholin-4-ylmethyl)-7-[(2~{S})-2-phenylpropoxy]chromen-2-one'>9ZX</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7lmr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lmr OCA], [https://pdbe.org/7lmr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lmr RCSB], [https://www.ebi.ac.uk/pdbsum/7lmr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lmr ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC50 values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key pi-pi stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.

Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.,Yan NL, Santos-Martins D, Nair R, Chu A, Wilson IA, Johnson KA, Forli S, Morgan GJ, Petrassi HM, Kelly JW J Med Chem. 2021 May 13;64(9):6273-6299. doi: 10.1021/acs.jmedchem.1c00339. Epub , 2021 May 3. PMID:33939422<ref>PMID:33939422</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Kelly JW]]
[[Category: Wilson IA]]
[[Category: Yan NL]]