9ax2: Difference between revisions
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==Structure of full-length amyloidogenic immunoglobulin light chain H9 in complex with 2-(1-methyl-3-oxo-5-(2-phenylpropoxy)isoindolin-2-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamate== | |||
<StructureSection load='9ax2' size='340' side='right'caption='[[9ax2]], [[Resolution|resolution]] 1.94Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9ax2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9AX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AX2 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]] 1.94Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AH6:2-{(1R)-1-methyl-3-oxo-5-[(2S)-2-phenylpropoxy]-1,3-dihydro-2H-isoindol-2-yl}ethyl+{[(3M)-3-(1H-imidazol-4-yl)phenyl]methyl}carbamate'>A1AH6</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=9ax2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ax2 OCA], [https://pdbe.org/9ax2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ax2 RCSB], [https://www.ebi.ac.uk/pdbsum/9ax2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ax2 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Kinetic stabilization of amyloidogenic immunoglobulin light chains (LCs) through small molecule binding may become the first treatment for the proteinopathy component of light chain amyloidosis (AL). Kinetic stabilizers selectively bind to the native state over the misfolding transition state, slowing denaturation. Prior lambda full-length LC dimer (FL LC(2)) kinetic stabilizers exhibited considerable plasma protein binding. We hypothesized that the coumarin "aromatic core" of the stabilizers was responsible for the undesirable plasma protein binding. Here, we describe structure-activity relationship (SAR) data initially focused on replacing the coumarin aromatic core. 2-pyridones proved suitable replacements. We subsequently optimized the "anchor substructure" in the context of 2-pyridones, resulting in potent lambda FL LC(2) kinetic stabilizers exhibiting reduced plasma protein binding. The 3-methyl- or 3-ethyl-3-phenylpyrrolidine-2-pyridone scaffold stabilized multiple AL patient-derived lambda FL LC(2)s in human plasma. This, coupled with X-ray crystallographic data, indicates that 3-alkyl-3-phenylpyrrolidine-2-pyridone-based stabilizers are promising candidates for treating the proteinopathy component of AL. | |||
Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains.,Lederberg OL, Yan NL, Sanchez J, Ren W, Ash C, Wilkens SJ, Qiu H, Qin B, Grant VH, Jackman AB, Stanfield RL, Wilson IA, Petrassi HM, Rhoades D, Kelly JW J Med Chem. 2024 Dec 12;67(23):21070-21105. doi: 10.1021/acs.jmedchem.4c01773. , Epub 2024 Dec 3. PMID:39626211<ref>PMID:39626211</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9ax2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Kelly JW]] | |||
[[Category: Lederberg OL]] | |||
[[Category: Stanfield RL]] | |||
[[Category: Wilson IA]] | |||
[[Category: Yan NL]] | |||
Latest revision as of 09:29, 18 December 2024
Structure of full-length amyloidogenic immunoglobulin light chain H9 in complex with 2-(1-methyl-3-oxo-5-(2-phenylpropoxy)isoindolin-2-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamateStructure of full-length amyloidogenic immunoglobulin light chain H9 in complex with 2-(1-methyl-3-oxo-5-(2-phenylpropoxy)isoindolin-2-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamate
Structural highlights
Publication Abstract from PubMedKinetic stabilization of amyloidogenic immunoglobulin light chains (LCs) through small molecule binding may become the first treatment for the proteinopathy component of light chain amyloidosis (AL). Kinetic stabilizers selectively bind to the native state over the misfolding transition state, slowing denaturation. Prior lambda full-length LC dimer (FL LC(2)) kinetic stabilizers exhibited considerable plasma protein binding. We hypothesized that the coumarin "aromatic core" of the stabilizers was responsible for the undesirable plasma protein binding. Here, we describe structure-activity relationship (SAR) data initially focused on replacing the coumarin aromatic core. 2-pyridones proved suitable replacements. We subsequently optimized the "anchor substructure" in the context of 2-pyridones, resulting in potent lambda FL LC(2) kinetic stabilizers exhibiting reduced plasma protein binding. The 3-methyl- or 3-ethyl-3-phenylpyrrolidine-2-pyridone scaffold stabilized multiple AL patient-derived lambda FL LC(2)s in human plasma. This, coupled with X-ray crystallographic data, indicates that 3-alkyl-3-phenylpyrrolidine-2-pyridone-based stabilizers are promising candidates for treating the proteinopathy component of AL. Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains.,Lederberg OL, Yan NL, Sanchez J, Ren W, Ash C, Wilkens SJ, Qiu H, Qin B, Grant VH, Jackman AB, Stanfield RL, Wilson IA, Petrassi HM, Rhoades D, Kelly JW J Med Chem. 2024 Dec 12;67(23):21070-21105. doi: 10.1021/acs.jmedchem.4c01773. , Epub 2024 Dec 3. PMID:39626211[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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