5MG9

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins.

Blanchet, G.Alili, D.Protte, A.Upert, G.Gilles, N.Tepshi, L.Stura, E.A.Mourier, G.Servent, D.

(2017) Sci Rep 7: 2701-2701

  • DOI: https://doi.org/10.1038/s41598-017-02953-0
  • Primary Citation of Related Structures:  
    5MG9

  • 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 1A -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 1 and α 2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.


  • Organizational Affiliation

    CEA Institut des Sciences du Vivant Frédéric Joliot, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Université Paris-Saclay, Gif-sur-Yvette, Paris, 91190, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
AncTx1-W28R/I38S65Dendroaspis angusticepsMutation(s): 0 
UniProt
Find proteins for P85092 (Dendroaspis angusticeps)
Explore P85092 
Go to UniProtKB:  P85092
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP85092
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YVR
Query on YVR

Download Ideal Coordinates CCD File 
H [auth A]gamma-Valerolactone
C5 H8 O2
GAEKPEKOJKCEMS-BYPYZUCNSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
G [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
PGO
Query on PGO

Download Ideal Coordinates CCD File 
B [auth A]S-1,2-PROPANEDIOL
C3 H8 O2
DNIAPMSPPWPWGF-VKHMYHEASA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.057α = 90
b = 41.057β = 90
c = 67.118γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-03
    Type: Initial release
  • Version 1.1: 2017-06-14
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description