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Structural plasticity and dynamic selectivity of acid-sensing ion channel–spider toxin complexes


Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is approximately 10 Å in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7 Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

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Figure 1: PcTx1 activates the chicken ASIC1a Δ13 construct.
Figure 2: Extensive interactions adhere PcTx1 to the Δ13 ion channel.
Figure 3: Conformational changes in the extracellular domain.
Figure 4: Structural rearrangements and ion selectivity of the transmembrane pores.
Figure 5: Cs + binding sites.
Figure 6: Schematic representation of gating.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Structures for low-pH and high-pH D13–PcTx1 complexes have been deposited in PDB under accession numbers 4FZ0 and 4FZ1, respectively.


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We appreciate assistance in the initial characterization of the action of PcTx1 on chicken ASIC1a by D. Samways and T. Egan, mass spectrometry analysis by D. King, together with comments from C. Jahr and R. MacKinnon. We are grateful to K. C. Garcia, C. Lee and A. Goehring for assistance with protein expression in mammalian cells. We thank L. Vaskalis for assistance with figures, H. Owen for help with manuscript preparation, H. Krishnamurthy for assistance in initial data collection, and Gouaux lab members for helpful discussion. This work was supported by an individual National Research Service Award from the National Institute of Neurological Disorders and Stroke (I.B.) and by the NIH (E.G.). E.G. is an investigator with the Howard Hughes Medical Institute.

Author information




I.B. and E.G. designed the project. I.B. performed protein purification, crystallography and electrophysiology. I.B. and E.G. wrote the manuscript.

Corresponding author

Correspondence to Eric Gouaux.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Table 1, Supplementary Figures 1-20 and legends for Supplementary Movies 1-2. (PDF 8864 kb)

Supplementary Movie 1

This movie shows the structural changes accompanying PcTx1 binding to the Δ13 construct at low pH (see Supplementary Information file for full legend). (MOV 10455 kb)

Supplementary Movie 2

This movie shows the structural changes accompanying PcTx1 binding to the Δ13 construct at high pH (see Supplementary Information file for full legend). (MOV 6413 kb)

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Baconguis, I., Gouaux, E. Structural plasticity and dynamic selectivity of acid-sensing ion channel–spider toxin complexes. Nature 489, 400–405 (2012).

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