7rtp: Difference between revisions
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==Structure of full-length human lambda-6A light chain JTO in complex with urea stabilizer 20 [1-(2-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)ethyl)-3-(pyridin-3-ylmethyl)urea]== | |||
<StructureSection load='7rtp' size='340' side='right'caption='[[7rtp]], [[Resolution|resolution]] 2.09Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RTP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RTP 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]] 2.09Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NY9:N-{2-[7-(diethylamino)-4-methyl-2-oxo-2H-1-benzopyran-3-yl]ethyl}-N-[(pyridin-3-yl)methyl]urea'>NY9</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=7rtp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rtp OCA], [https://pdbe.org/7rtp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rtp RCSB], [https://www.ebi.ac.uk/pdbsum/7rtp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rtp ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In immunoglobulin light chain (LC) amyloidosis, the misfolding, or misfolding and misassembly of LC a protein or fragments thereof resulting from aberrant endoproteolysis, causes organ damage to patients. A small molecule "kinetic stabilizer" drug could slow or stop these processes and improve prognosis. We previously identified coumarin-based kinetic stabilizers of LCs that can be divided into four components, including a "linker module" and "distal substructure". Our prior studies focused on characterizing carbamate, hydantoin, and spirocyclic urea linker modules, which bind in a solvent-exposed site at the VL-VL domain interface of the LC dimer. Here, we report structure-activity relationship data on 7-diethylamino coumarin-based kinetic stabilizers. This substructure occupies the previously characterized "anchor cavity" and the "aromatic slit". The potencies of amide and urea linker modules terminating in a variety of distal substructures attached at the 3-position of this coumarin ring were assessed. Surprisingly, crystallographic data on a 7-diethylamino coumarin-based kinetic stabilizer reveals that the urea linker module and distal substructure attached at the 3-position bind a solvent-exposed region of the full-length LC dimer distinct from previously characterized sites. Our results further elaborate the small-molecule binding surface of LCs that could be occupied by potent and selective LC kinetic stabilizers. | |||
Amyloidogenic immunoglobulin light chain kinetic stabilizers comprising a simple urea linker module reveal a novel binding sub-site.,Yan NL, Nair R, Chu A, Wilson IA, Johnson KA, Morgan GJ, Kelly JW Bioorg Med Chem Lett. 2022 Jan 19;60:128571. doi: 10.1016/j.bmcl.2022.128571. PMID:35065233<ref>PMID:35065233</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Kelly | <div class="pdbe-citations 7rtp" style="background-color:#fffaf0;"></div> | ||
[[Category: Wilson | == References == | ||
[[Category: Yan | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Kelly JW]] | |||
[[Category: Wilson IA]] | |||
[[Category: Yan NL]] | |||