7rtp: Difference between revisions
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<StructureSection load='7rtp' size='340' side='right'caption='[[7rtp]], [[Resolution|resolution]] 2.09Å' scene=''> | <StructureSection load='7rtp' size='340' side='right'caption='[[7rtp]], [[Resolution|resolution]] 2.09Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <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> | </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='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> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Kelly JW]] | [[Category: Kelly JW]] | ||
[[Category: Wilson IA]] | [[Category: Wilson IA]] | ||
[[Category: Yan NL]] | [[Category: Yan NL]] | ||
Latest revision as of 14:38, 30 October 2024
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]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]
Structural highlights
Publication Abstract from PubMedIn 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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