4AEI

Crystal structure of the AaHII-Fab4C1 complex

Summary for 4AEI

• Entry DOI: 10.2210/pdb4aei/pdb
• Related: 1AHO 1PTX 1SEG 4AEH
• Descriptor: ALPHA-MAMMAL TOXIN AAH2, FAB ANTIBODY HEAVY CHAIN, FAB ANTIBODY LIGHT CHAIN, ... (6 entities in total)
• Functional Keywords: immune system-toxin complex, alpha-toxin, conformational rearrangement, combining site, epitope, pharmacological site, venom, voltage-activated sodium channel, immune system/toxin
• Biological source: ANDROCTONUS AUSTRALIS HECTOR (FAT-TAILED SCORPION); More
• Cellular location: Secreted: P01484
• Total number of polymer chains: 9
• Total formula weight: 169166.50

Authors

Fabrichny, I.P.,Mondielli, G.,Conrod, S.,Martin-Eauclaire, M.F.,Bourne, Y.,Marchot, P. (deposition date: 2012-01-10, release date: 2012-03-07, Last modification date: 2024-11-13)

Primary citation

Fabrichny, I.P.,Mondielli, G.,Conrod, S.,Martin-Eauclaire, M.F.,Bourne, Y.,Marchot, P.
Structural Insights Into Antibody Sequestering and Neutralizing of Na+-Channel & [Alpha]-Type Modulator from Old-World Scorpion Venom
J.Biol.Chem., 287:14136-, 2012

PubMed Abstract: The Old World scorpion Androctonus australis hector (Aah) produces one of the most lethal venoms for humans. Peptidic α-toxins AahI to AahIV are responsible for its potency, with AahII accounting for half of it. All four toxins are high affinity blockers of the fast inactivation phase of mammalian voltage-activated Na(+) channels. However, the high antigenic polymorphism of α-toxins prevents production of a polyvalent neutralizing antiserum, whereas the determinants dictating their trapping by neutralizing antibodies remain elusive. From an anti-AahII mAb, we generated an antigen binding fragment (Fab) with high affinity and selectivity for AahII and solved a 2.3 Å-resolution crystal structure of the complex. Sequestering of the C-terminal region of the bound toxin within a groove formed by the Fab combining loops is associated with a toxin orientation and main and side chain conformations that dictate the AahII antigenic specificity and efficient neutralization. From an anti-AahI mAb, we also preformed and crystallized a high affinity AahI-Fab complex. The 1.6 Å-resolution structure solved revealed a Fab molecule devoid of a bound AahI and with combining loops involved in packing interactions, denoting expulsion of the bound antigen upon crystal formation. Comparative analysis of the groove-like combining site of the toxin-bound anti-AahII Fab and planar combining surface of the unbound anti-AahI Fab along with complementary data from a flexible docking approach suggests occurrence of distinctive trapping orientations for the two toxins relative to their respective Fab. This study provides complementary templates for designing new molecules aimed at capturing Aah α-toxins and suitable for immunotherapy.

PubMed: 22371498
DOI: 10.1074/JBC.M111.315382

Experimental method

X-RAY DIFFRACTION (2.3 Å)