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9hub
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==D11 mAbs bound to alpha-Bungarotoxin at pH 7.5== | |
| + | <StructureSection load='9hub' size='340' side='right'caption='[[9hub]], [[Resolution|resolution]] 1.33Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9hub]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bungarus_multicinctus Bungarus multicinctus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9HUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HUB 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]] 1.33Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=9hub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hub OCA], [https://pdbe.org/9hub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hub RCSB], [https://www.ebi.ac.uk/pdbsum/9hub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hub ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/3L21A_BUNMU 3L21A_BUNMU] Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).<ref>PMID:16549768</ref> <ref>PMID:25634239</ref> <ref>PMID:9305882</ref> <ref>PMID:9840221</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Antibodies that bind in a pH-dependent manner to their antigens show promise for enhanced neutralization potency and blocking capacity against extracellular targets. However, because the mechanisms governing pH-dependent antigen binding remain poorly understood, engineering approaches are often limited to incorporating histidine residues in the antibody complementarity-determining regions. Here, we use a panel of human monoclonal antibodies with neutralizing activity to long-chain alpha-neurotoxins (LNTxs) to investigate pH-dependent antigen binding. The antibodies vary in their light chains but have conserved histidine residues in their variable domains, allowing us to explore how other residues may affect pH dependence. Comparative structural and molecular dynamics studies between two antibodies with and without pH-dependent antigen-binding properties reveal that both antibodies neutralize LNTxs by mimicking LNTx-receptor interactions through their heavy chains. We hypothesize that part of the pH-dependency can be controlled by the light chain through modulation of water access to residues at the heavy-light-chain interface. We show that pH-dependent antigen-binding properties can be introduced into monoclonal antibodies through the substitution of selected residues at the heavy-light-chain interface. Specifically, we replaced tyrosine residues in the light chain with small polar and apolar amino acid residues in a structurally related anti-LNTx antibody with limited inherent pH-dependent antigen-binding properties, and found that these smaller substitutions enhanced pH-dependence more effectively than histidine substitutions alone. Our findings suggest a strategy for engineering pH-dependent antigen binding in antibodies that goes beyond the exclusive use of histidine doping. | ||
| - | + | Rational design of antibodies with pH-dependent antigen-binding properties using structural insights from broadly neutralizing antibodies against alpha-neurotoxins.,Wade J, Strancar N, Fernandez-Quintero ML, Siebenhaar S, Jansen T, Meier EPW, Jenkins TP, Bjorn SP, Nguyen GTT, Lomonte B, Gutierrez JM, Sorensen CV, Loeffler JR, Paul A, Tulika T, Arnsdorf J, Schoffelen S, Lundquist EVS, Sorensen J, Ward AB, Voldborg BG, Bohn MF, Rivera-de-Torre E, Morth JP, Laustsen AH MAbs. 2025 Dec;17(1):2553624. doi: 10.1080/19420862.2025.2553624. Epub 2025 Sep , 11. PMID:40936197<ref>PMID:40936197</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9hub" style="background-color:#fffaf0;"></div> |
| - | [[Category: Bohn | + | == References == |
| - | [[Category: Laustsen | + | <references/> |
| - | [[Category: Wade | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Bungarus multicinctus]] | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bohn MF]] | ||
| + | [[Category: Laustsen AH]] | ||
| + | [[Category: Morth JP]] | ||
| + | [[Category: Wade JW]] | ||
Current revision
D11 mAbs bound to alpha-Bungarotoxin at pH 7.5
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