7lmn: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='7lmn' size='340' side='right'caption='[[7lmn]], [[Resolution|resolution]] 2.01Å' scene=''> | <StructureSection load='7lmn' size='340' side='right'caption='[[7lmn]], [[Resolution|resolution]] 2.01Å' 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=7LMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LMN 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]] 2.01Å</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]] 2.01Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NY3:2-[7-(diethylamino)-4-methyl-2-oxidanylidene-chromen-3-yl]ethyl+~{N}-[[3-(1~{H}-imidazol-5-yl)phenyl]methyl]carbamate'>NY3</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=NY3:2-[7-(diethylamino)-4-methyl-2-oxidanylidene-chromen-3-yl]ethyl+~{N}-[[3-(1~{H}-imidazol-5-yl)phenyl]methyl]carbamate'>NY3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
| Line 24: | Line 24: | ||
__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 14:33, 30 October 2024
Structure of full-length human lambda-6A light chain JTO in complex with stabilizer 26 [2-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamate]Structure of full-length human lambda-6A light chain JTO in complex with stabilizer 26 [2-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamate]
Structural highlights
Publication Abstract from PubMedIn 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||