View source for 8va0


==X-ray crystal structure of JGFN4 N76D complexed with fentanyl in dimer form==
<StructureSection load='8va0' size='340' side='right'caption='[[8va0]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8va0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Camelidae Camelidae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8VA0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8VA0 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7V7:N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide'>7V7</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=8va0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8va0 OCA], [https://pdbe.org/8va0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8va0 RCSB], [https://www.ebi.ac.uk/pdbsum/8va0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8va0 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad. Current treatments consist of opioid receptor agonists and antagonists, which are safe and effective but still suffer from some limitations. Murine and humanized monoclonal antibodies (mAb) have emerged as an alternative and complementary strategy to reverse and prevent opioid-induced respiratory depression. To explore antibody applications beyond traditional heavy-light chain mAbs, we identified and biophysically characterized a novel single-domain antibody specific for fentanyl from a camelid variable-heavy-heavy (VHH) domain phage display library. Structural data suggested that VHH binding to fentanyl was facilitated by a unique domain-swapped dimerization mechanism, which accompanied a rearrangement of complementarity-determining region loops leading to the formation of a fentanyl-binding pocket. Structure-guided mutagenesis further identified an amino acid substitution that improved the affinity and relaxed the requirement for dimerization of the VHH in fentanyl binding. Our studies demonstrate VHH engagement of an opioid and inform on how to further engineer a VHH for enhanced stability and efficacy, laying the groundwork for exploring the in vivo applications of VHH-based biologics against OUD and overdose.

Identification and biophysical characterization of a novel domain-swapped camelid antibody specific for fentanyl.,Gallant JP, Hicks D, Shi K, Moeller NH, Hoppe B, Lake EW, Baehr C, Pravetoni M, Aihara H, LeBeau AM J Biol Chem. 2024 Jun 28;300(8):107502. doi: 10.1016/j.jbc.2024.107502. PMID:38945452<ref>PMID:38945452</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8va0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Camelidae]]
[[Category: Large Structures]]
[[Category: Aihara H]]
[[Category: Moller N]]
[[Category: Shi K]]