3fev

From Proteopedia

(Difference between revisions)

Revision as of 15:29, 1 November 2023

Crystal structure of the chimeric muscarinic toxin MT7 with loop 1 from MT1.

Structural highlights

3fev is a 3 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 1.3Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

3SIM7_DENAN Binds irreversibly and specifically to an allosteric site of the muscarinic acetylcholine M1 receptor (CHRM1).^[1] ^[2] ^[3] ^[4] 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).^[5] ^[6] ^[7] ^[8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

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^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nasman J, Jolkkonen M, Ammoun S, Karlsson E, Akerman KE. Recombinant expression of a selective blocker of M(1) muscarinic receptors. Biochem Biophys Res Commun. 2000 May 10;271(2):435-9. PMID:10799315 doi:http://dx.doi.org/10.1006/bbrc.2000.2657
↑ Krajewski JL, Dickerson IM, Potter LT. Site-directed mutagenesis of m1-toxin1: two amino acids responsible for stable toxin binding to M(1) muscarinic receptors. Mol Pharmacol. 2001 Oct;60(4):725-31. PMID:11562434
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Fruchart-Gaillard C, Mourier G, Blanchet G, Vera L, Gilles N, Menez R, Marcon E, Stura EA, Servent D. Engineering of three-finger fold toxins creates ligands with original pharmacological profiles for muscarinic and adrenergic receptors. PLoS One. 2012;7(6):e39166. Epub 2012 Jun 14. PMID:22720062 doi:10.1371/journal.pone.0039166

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3fev"

@@ Line 3: / Line 3: @@
 <StructureSection load='3fev' size='340' side='right'caption='[[3fev]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3fev]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FEV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FEV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3fev]] is a 3 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=3FEV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FEV FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2vlw|2vlw]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=3fev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fev OCA], [https://pdbe.org/3fev PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fev RCSB], [https://www.ebi.ac.uk/pdbsum/3fev PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fev ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/TXM1_DENAN TXM1_DENAN]] Binds irreversibly to M1 (CHRM1) muscarinic acetylcholine receptors, and reveals a slightly weaker effect at M3 (CHRM3) receptor.
+[https://www.uniprot.org/uniprot/3SIM7_DENAN 3SIM7_DENAN] Binds irreversibly and specifically to an allosteric site of the muscarinic acetylcholine M1 receptor (CHRM1).<ref>PMID:10799315</ref> <ref>PMID:11562434</ref> <ref>PMID:12488533</ref> <ref>PMID:21557730</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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 33: @@
 __TOC__
 </StructureSection>
+[[Category: Dendroaspis angusticeps]]
 [[Category: Large Structures]]
-[[Category: Fruchart-Gaillard, C]]
+[[Category: Fruchart-Gaillard C]]
-[[Category: Menez, A]]
+[[Category: Menez A]]
-[[Category: Menez, R]]
+[[Category: Menez R]]
-[[Category: Mourier, G]]
+[[Category: Mourier G]]
-[[Category: Servant, D]]
+[[Category: Servant D]]
-[[Category: Stura, E A]]
+[[Category: Stura EA]]
-[[Category: Acetylcholine receptor inhibitor]]
-[[Category: Chimera]]
-[[Category: Green mamba snake toxin]]
-[[Category: Hm1 muscarinic receptor]]
-[[Category: Muscarinic toxin]]
-[[Category: Neurotoxin]]
-[[Category: Postsynaptic neurotoxin]]
-[[Category: Secreted]]
-[[Category: Toxin]]

3fev

From Proteopedia

Revision as of 15:29, 1 November 2023

Crystal structure of the chimeric muscarinic toxin MT7 with loop 1 from MT1.

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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