4do8: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4do8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dendroaspis_angusticeps Dendroaspis angusticeps]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DO8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DO8 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4do8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dendroaspis_angusticeps Dendroaspis angusticeps]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DO8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DO8 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene></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]] 1.802&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</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=4do8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4do8 OCA], [https://pdbe.org/4do8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4do8 RCSB], [https://www.ebi.ac.uk/pdbsum/4do8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4do8 ProSAT]</span></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=4do8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4do8 OCA], [https://pdbe.org/4do8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4do8 RCSB], [https://www.ebi.ac.uk/pdbsum/4do8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4do8 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/3SIM1_DENAN 3SIM1_DENAN]] Shows a non-competitive interaction with adrenergic and muscarinic receptors. Binds to alpha-2b (ADRA2B) (IC(50)=2.3 nM), alpha-1a (ADRA1A), alpha-1b (ADRA1B), and alpha-2c (ADRA2C) adrenergic receptors. Reversibly binds to M1 (CHRM1) muscarinic acetylcholine receptors, probably by interacting with the orthosteric site (PubMed:7778123, PubMed:12488533, PubMed:24793485). Also reveals a slightly weaker effect at M3 (CHRM3) and M4 (CHRM4) receptors (PubMed:7778123, PubMed:12488533, PubMed:24793485). The order of potency is ADRA2B>>CHRM1>ADRA1A>ADRA1B>ADRA2C/CHRM4 (PubMed:24793485).<ref>PMID:12488533</ref> <ref>PMID:21557730</ref> <ref>PMID:24793485</ref> <ref>PMID:7778123</ref>
[https://www.uniprot.org/uniprot/3SIM1_DENAN 3SIM1_DENAN] Shows a non-competitive interaction with adrenergic and muscarinic receptors. Binds to alpha-2b (ADRA2B) (IC(50)=2.3 nM), alpha-1a (ADRA1A), alpha-1b (ADRA1B), and alpha-2c (ADRA2C) adrenergic receptors. Reversibly binds to M1 (CHRM1) muscarinic acetylcholine receptors, probably by interacting with the orthosteric site (PubMed:7778123, PubMed:12488533, PubMed:24793485). Also reveals a slightly weaker effect at M3 (CHRM3) and M4 (CHRM4) receptors (PubMed:7778123, PubMed:12488533, PubMed:24793485). The order of potency is ADRA2B>>CHRM1>ADRA1A>ADRA1B>ADRA2C/CHRM4 (PubMed:24793485).<ref>PMID:12488533</ref> <ref>PMID:21557730</ref> <ref>PMID:24793485</ref> <ref>PMID:7778123</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test "loop grafting," a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the alpha(1A)-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and alpha(1A)-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles.
 
Engineering of three-finger fold toxins creates ligands with original pharmacological profiles for muscarinic and adrenergic receptors.,Fruchart-Gaillard C, Mourier G, Blanchet G, Vera L, Gilles N, Menez R, Marcon E, Stura EA, Servent D PLoS One. 2012;7(6):e39166. Epub 2012 Jun 14. PMID:22720062<ref>PMID:22720062</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4do8" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Revision as of 09:47, 3 April 2024

Crystal structure of the muscarinic toxin MT1Crystal structure of the muscarinic toxin MT1

Structural highlights

4do8 is a 2 chain structure with sequence from Dendroaspis angusticeps. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.802Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

3SIM1_DENAN Shows a non-competitive interaction with adrenergic and muscarinic receptors. Binds to alpha-2b (ADRA2B) (IC(50)=2.3 nM), alpha-1a (ADRA1A), alpha-1b (ADRA1B), and alpha-2c (ADRA2C) adrenergic receptors. Reversibly binds to M1 (CHRM1) muscarinic acetylcholine receptors, probably by interacting with the orthosteric site (PubMed:7778123, PubMed:12488533, PubMed:24793485). Also reveals a slightly weaker effect at M3 (CHRM3) and M4 (CHRM4) receptors (PubMed:7778123, PubMed:12488533, PubMed:24793485). The order of potency is ADRA2B>>CHRM1>ADRA1A>ADRA1B>ADRA2C/CHRM4 (PubMed:24793485).[1] [2] [3] [4]

References

  1. ↑ Mourier G, Dutertre S, Fruchart-Gaillard C, Menez A, Servent D. Chemical synthesis of MT1 and MT7 muscarinic toxins: critical role of Arg-34 in their interaction with M1 muscarinic receptor. Mol Pharmacol. 2003 Jan;63(1):26-35. PMID:12488533
  2. ↑ Nareoja K, Kukkonen JP, Rondinelli S, Toivola DM, Meriluoto J, Nasman J. Adrenoceptor activity of muscarinic toxins identified from mamba venoms. Br J Pharmacol. 2011 Sep;164(2b):538-50. doi: 10.1111/j.1476-5381.2011.01468.x. PMID:21557730 doi:http://dx.doi.org/10.1111/j.1476-5381.2011.01468.x
  3. ↑ Blanchet G, Collet G, Mourier G, Gilles N, Fruchart-Gaillard C, Marcon E, Servent D. Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: case of aminergic toxins. Biochimie. 2014 Aug;103:109-17. doi: 10.1016/j.biochi.2014.04.009. Epub 2014 May , 1. PMID:24793485 doi:http://dx.doi.org/10.1016/j.biochi.2014.04.009
  4. ↑ Kornisiuk E, Jerusalinsky D, Cervenansky C, Harvey AL. Binding of muscarinic toxins MTx1 and MTx2 from the venom of the green mamba Dendroaspis angusticeps to cloned human muscarinic cholinoceptors. Toxicon. 1995 Jan;33(1):11-8. PMID:7778123

4do8, resolution 1.80Å

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