5mg9: Difference between revisions

Latest revision as of 18:42, 1 November 2023

Putative Ancestral Mamba toxin 1 (AncTx1-W28R/I38S)

Structural highlights

5mg9 is a 1 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 1.801Å
Ligands:	EDO, PGO, SO4, YVR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

3SI1A_DENAN Orthosteric antagonist of the alpha-1A adrenergic receptor (ADRA1A) with an affinity of 0.35 nM (PubMed:20015090). Has also affinity for ADRA1B > ADRA2C > ADRA1D (PubMed:23935897). Acts as a relaxant of smooth muscle. Reduces prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects (PubMed:23005263).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various alpha-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting task of producing and screening an overwhelming number of variants generated by a classical protein engineering strategy, we accepted the challenge of resurrecting ancestral proteins, likely to have possessed functional properties. This innovative approach that exploits molecular evolution models to efficiently guide protein engineering, has allowed us to generate a small library of six ancestral toxin (AncTx) variants and associate their pharmacological profiles to key functional substitutions. Among these variants, we identified AncTx1 as the most alpha1A-adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three alpha2 adrenoceptor subtypes. Three positions in the rho-Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the alpha1 and alpha2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.

Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins.,Blanchet G, Alili D, Protte A, Upert G, Gilles N, Tepshi L, Stura EA, Mourier G, Servent D Sci Rep. 2017 Jun 2;7(1):2701. doi: 10.1038/s41598-017-02953-0. PMID:28578406^[5]

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

References

↑ Quinton L, Girard E, Maiga A, Rekik M, Lluel P, Masuyer G, Larregola M, Marquer C, Ciolek J, Magnin T, Wagner R, Molgo J, Thai R, Fruchart-Gaillard C, Mourier G, Chamot-Rooke J, Menez A, Palea S, Servent D, Gilles N. Isolation and pharmacological characterization of AdTx1, a natural peptide displaying specific insurmountable antagonism of the alpha1A-adrenoceptor. Br J Pharmacol. 2010 Jan 1;159(2):316-25. doi: 10.1111/j.1476-5381.2009.00532.x. , Epub 2009 Dec 15. PMID:20015090 doi:https://dx.doi.org/10.1111/j.1476-5381.2009.00532.x
↑ Maiga A, Mourier G, Quinton L, Rouget C, Gales C, Denis C, Lluel P, Senard JM, Palea S, Servent D, Gilles N. G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors. Toxicon. 2012 Mar 15;59(4):487-96. doi: 10.1016/j.toxicon.2011.03.009. Epub 2011 , Mar 22. PMID:21419153 doi:https://dx.doi.org/10.1016/j.toxicon.2011.03.009
↑ Palea S, Maiga A, Guilloteau V, Rekik M, Guerard M, Rouget C, Rischmann P, Botto H, Camparo P, Lluel P, Gilles N. Effects of rho-Da1a a peptidic alpha(1) (A) -adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats. Br J Pharmacol. 2013 Feb;168(3):618-31. doi: 10.1111/j.1476-5381.2012.02231.x. PMID:23005263 doi:https://dx.doi.org/10.1111/j.1476-5381.2012.02231.x
↑ Maiga A, Merlin J, Marcon E, Rouget C, Larregola M, Gilquin B, Fruchart-Gaillard C, Lajeunesse E, Marchetti C, Lorphelin A, Bellanger L, Summers RJ, Hutchinson DS, Evans BA, Servent D, Gilles N. Orthosteric binding of rho-Da1a, a natural peptide of snake venom interacting selectively with the alpha1A-adrenoceptor. PLoS One. 2013 Jul 25;8(7):e68841. doi: 10.1371/journal.pone.0068841. Print 2013. PMID:23935897 doi:https://dx.doi.org/10.1371/journal.pone.0068841
↑ Blanchet G, Alili D, Protte A, Upert G, Gilles N, Tepshi L, Stura EA, Mourier G, Servent D. Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins. Sci Rep. 2017 Jun 2;7(1):2701. doi: 10.1038/s41598-017-02953-0. PMID:28578406 doi:https://dx.doi.org/10.1038/s41598-017-02953-0

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Quinton L, Girard E, Maiga A, Rekik M, Lluel P, Masuyer G, Larregola M, Marquer C, Ciolek J, Magnin T, Wagner R, Molgo J, Thai R, Fruchart-Gaillard C, Mourier G, Chamot-Rooke J, Menez A, Palea S, Servent D, Gilles N. Isolation and pharmacological characterization of AdTx1, a natural peptide displaying specific insurmountable antagonism of the alpha1A-adrenoceptor. Br J Pharmacol. 2010 Jan 1;159(2):316-25. doi: 10.1111/j.1476-5381.2009.00532.x. , Epub 2009 Dec 15. PMID:20015090 doi:https://dx.doi.org/10.1111/j.1476-5381.2009.00532.x

[2] Maiga A, Mourier G, Quinton L, Rouget C, Gales C, Denis C, Lluel P, Senard JM, Palea S, Servent D, Gilles N. G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors. Toxicon. 2012 Mar 15;59(4):487-96. doi: 10.1016/j.toxicon.2011.03.009. Epub 2011 , Mar 22. PMID:21419153 doi:https://dx.doi.org/10.1016/j.toxicon.2011.03.009

[3] Palea S, Maiga A, Guilloteau V, Rekik M, Guerard M, Rouget C, Rischmann P, Botto H, Camparo P, Lluel P, Gilles N. Effects of rho-Da1a a peptidic alpha(1) (A) -adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats. Br J Pharmacol. 2013 Feb;168(3):618-31. doi: 10.1111/j.1476-5381.2012.02231.x. PMID:23005263 doi:https://dx.doi.org/10.1111/j.1476-5381.2012.02231.x

[4] Maiga A, Merlin J, Marcon E, Rouget C, Larregola M, Gilquin B, Fruchart-Gaillard C, Lajeunesse E, Marchetti C, Lorphelin A, Bellanger L, Summers RJ, Hutchinson DS, Evans BA, Servent D, Gilles N. Orthosteric binding of rho-Da1a, a natural peptide of snake venom interacting selectively with the alpha1A-adrenoceptor. PLoS One. 2013 Jul 25;8(7):e68841. doi: 10.1371/journal.pone.0068841. Print 2013. PMID:23935897 doi:https://dx.doi.org/10.1371/journal.pone.0068841

[5] Blanchet G, Alili D, Protte A, Upert G, Gilles N, Tepshi L, Stura EA, Mourier G, Servent D. Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins. Sci Rep. 2017 Jun 2;7(1):2701. doi: 10.1038/s41598-017-02953-0. PMID:28578406 doi:https://dx.doi.org/10.1038/s41598-017-02953-0

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[2]

[3]

[4]

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@@ Line 3: / Line 3: @@
 <StructureSection load='5mg9' size='340' side='right'caption='[[5mg9]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mg9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MG9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MG9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mg9]] is a 1 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=5MG9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MG9 FirstGlance]. <br>
-</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>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YVR:GAMMA-VALEROLACTONE'>YVR</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]] 1.801&#8491;</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=5mg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mg9 OCA], [http://pdbe.org/5mg9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mg9 RCSB], [http://www.ebi.ac.uk/pdbsum/5mg9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mg9 ProSAT]</span></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>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YVR:GAMMA-VALEROLACTONE'>YVR</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=5mg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mg9 OCA], [https://pdbe.org/5mg9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mg9 RCSB], [https://www.ebi.ac.uk/pdbsum/5mg9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mg9 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/3SI1A_DENAN 3SI1A_DENAN] Orthosteric antagonist of the alpha-1A adrenergic receptor (ADRA1A) with an affinity of 0.35 nM (PubMed:20015090). Has also affinity for ADRA1B > ADRA2C > ADRA1D (PubMed:23935897). Acts as a relaxant of smooth muscle. Reduces prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects (PubMed:23005263).<ref>PMID:20015090</ref> <ref>PMID:21419153</ref> <ref>PMID:23005263</ref> <ref>PMID:23935897</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Dendroaspis angusticeps]]
 [[Category: Large Structures]]
-[[Category: Blanchet, G]]
+[[Category: Blanchet G]]
-[[Category: Mourier, G]]
+[[Category: Mourier G]]
-[[Category: Servent, D]]
+[[Category: Servent D]]
-[[Category: Stura, E A]]
+[[Category: Stura EA]]
-[[Category: Tepshi, L]]
+[[Category: Tepshi L]]
-[[Category: Aminergic toxin]]
-[[Category: Ancestral mamba snake toxin]]
-[[Category: Ancestral toxin resurrection and engineering]]
-[[Category: Three-finger fold]]
-[[Category: Toxin]]

5mg9: Difference between revisions

Latest revision as of 18:42, 1 November 2023

Putative Ancestral Mamba toxin 1 (AncTx1-W28R/I38S)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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