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==CryoEM structure of human alpha4beta2 nicotinic acetylcholine receptor with varenicline in complex with anti-BRIL synthetic antibody BAK5== | ==CryoEM structure of human alpha4beta2 nicotinic acetylcholine receptor with varenicline in complex with anti-BRIL synthetic antibody BAK5== | ||
<StructureSection load='6usf' size='340' side='right'caption='[[6usf]]' scene=''> | <StructureSection load='6usf' size='340' side='right'caption='[[6usf]], [[Resolution|resolution]] 3.87Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6USF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6USF FirstGlance]. <br> | <table><tr><td colspan='2'>[[6usf]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6USF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6USF FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6usf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6usf OCA], [http://pdbe.org/6usf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6usf RCSB], [http://www.ebi.ac.uk/pdbsum/6usf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6usf ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QMR:VARENICLINE'>QMR</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6cbv|6cbv]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHRNA4, NACRA4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895]), CHRNB2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6usf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6usf OCA], [http://pdbe.org/6usf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6usf RCSB], [http://www.ebi.ac.uk/pdbsum/6usf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6usf ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[http://www.uniprot.org/uniprot/ACHA4_HUMAN ACHA4_HUMAN]] Autosomal dominant nocturnal frontal lobe epilepsy. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/ACHB2_HUMAN ACHB2_HUMAN]] Defects in CHRNB2 are the cause of nocturnal frontal lobe epilepsy type 3 (ENFL3) [MIM:[http://omim.org/entry/605375 605375]]. ENFL3 is an autosomal dominant epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements.<ref>PMID:11062464</ref> <ref>PMID:11104662</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ACHA4_HUMAN ACHA4_HUMAN]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.<ref>PMID:22361591</ref> [[http://www.uniprot.org/uniprot/ACHB2_HUMAN ACHB2_HUMAN]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodiun ions.<ref>PMID:22361591</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction. Negative stain and cryoEM data of several examples of BRIL-membrane protein chimera highlight the effectiveness of the sABs as universal fiducial marks. Taken together with a cryoEM structure of sAB bound human nicotinic acetylcholine receptor, this work demonstrates that these anti-BRIL sABs can greatly enhance the particle properties leading to improved cryoEM outcomes, especially for challenging membrane proteins. | |||
Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins.,Mukherjee S, Erramilli SK, Ammirati M, Alvarez FJD, Fennell KF, Purdy MD, Skrobek BM, Radziwon K, Coukos J, Kang Y, Dutka P, Gao X, Qiu X, Yeager M, Eric Xu H, Han S, Kossiakoff AA Nat Commun. 2020 Mar 27;11(1):1598. doi: 10.1038/s41467-020-15363-0. PMID:32221310<ref>PMID:32221310</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6usf" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bacillus coli migula 1895]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Alvarez | [[Category: Alvarez, F J.D]] | ||
[[Category: Ammirati M]] | [[Category: Ammirati, M]] | ||
[[Category: Han S]] | [[Category: Han, S]] | ||
[[Category: Kossiakoff | [[Category: Kossiakoff, A A]] | ||
[[Category: Mukherjee S]] | [[Category: Mukherjee, S]] | ||
[[Category: Acetylcholine receptor]] | |||
[[Category: Anti-bril synthetic antibody]] | |||
[[Category: Membrane protein]] | |||
[[Category: Membrane protein-immune system complex]] | |||
[[Category: Nicotine]] | |||
[[Category: Varenicline]] | |||
Latest revision as of 09:37, 6 May 2020
CryoEM structure of human alpha4beta2 nicotinic acetylcholine receptor with varenicline in complex with anti-BRIL synthetic antibody BAK5CryoEM structure of human alpha4beta2 nicotinic acetylcholine receptor with varenicline in complex with anti-BRIL synthetic antibody BAK5
Structural highlights
Disease[ACHA4_HUMAN] Autosomal dominant nocturnal frontal lobe epilepsy. The disease is caused by mutations affecting the gene represented in this entry. [ACHB2_HUMAN] Defects in CHRNB2 are the cause of nocturnal frontal lobe epilepsy type 3 (ENFL3) [MIM:605375]. ENFL3 is an autosomal dominant epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements.[1] [2] Function[ACHA4_HUMAN] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.[3] [ACHB2_HUMAN] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodiun ions.[4] Publication Abstract from PubMedWe propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction. Negative stain and cryoEM data of several examples of BRIL-membrane protein chimera highlight the effectiveness of the sABs as universal fiducial marks. Taken together with a cryoEM structure of sAB bound human nicotinic acetylcholine receptor, this work demonstrates that these anti-BRIL sABs can greatly enhance the particle properties leading to improved cryoEM outcomes, especially for challenging membrane proteins. Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins.,Mukherjee S, Erramilli SK, Ammirati M, Alvarez FJD, Fennell KF, Purdy MD, Skrobek BM, Radziwon K, Coukos J, Kang Y, Dutka P, Gao X, Qiu X, Yeager M, Eric Xu H, Han S, Kossiakoff AA Nat Commun. 2020 Mar 27;11(1):1598. doi: 10.1038/s41467-020-15363-0. PMID:32221310[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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