View source for 5mg9


==Putative Ancestral Mamba toxin 1 (AncTx1-W28R/I38S)==
<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 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='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='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> 
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== 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<ref>PMID:28578406</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5mg9" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Dendroaspis angusticeps]]
[[Category: Large Structures]]
[[Category: Blanchet G]]
[[Category: Mourier G]]
[[Category: Servent D]]
[[Category: Stura EA]]
[[Category: Tepshi L]]