5MG9

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

5MG9 の概要

• エントリーDOI: 10.2210/pdb5mg9/pdb
• 分子名称: AncTx1-W28R/I38S, S-1,2-PROPANEDIOL, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: ancestral mamba snake toxin, three-finger fold, ancestral toxin resurrection and engineering, aminergic toxin, toxin
• 由来する生物種: Dendroaspis angusticeps (Eastern green mamba)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7877.88

構造登録者

Stura, E.A.,Tepshi, L.,Blanchet, G.,Mourier, G.,Servent, D. (登録日: 2016-11-21, 公開日: 2017-05-03, 最終更新日: 2024-11-06)

主引用文献

Blanchet, G.,Alili, D.,Protte, A.,Upert, G.,Gilles, N.,Tepshi, L.,Stura, E.A.,Mourier, G.,Servent, D.
Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins.
Sci Rep, 7:2701-2701, 2017

PubMed Abstract: Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various α-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 α-adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three α2 adrenoceptor subtypes. Three positions in the ρ-Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the α and α adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.

PubMed: 28578406
DOI: 10.1038/s41598-017-02953-0

実験手法

X-RAY DIFFRACTION (1.801 Å)