Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

A Dynamic Pharmacophore Drives the Interaction between Psalmotoxin-1 and the Putative Drug Target Acid-Sensing Ion Channel 1a

Natalie J. Saez, Mehdi Mobli, Michael Bieri, Irène R. Chassagnon, Alpeshkumar K. Malde, Roland Gamsjaeger, Alan E. Mark, Paul R. Gooley, Lachlan D. Rash and Glenn F. King
Molecular Pharmacology November 2011, 80 (5) 796-808; DOI: https://doi.org/10.1124/mol.111.072207
Natalie J. Saez
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mehdi Mobli
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Bieri
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Irène R. Chassagnon
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alpeshkumar K. Malde
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roland Gamsjaeger
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan E. Mark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul R. Gooley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lachlan D. Rash
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glenn F. King
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Acid-sensing ion channel 1a (ASIC1a) is a primary acid sensor in the peripheral and central nervous system. It has been implicated as a novel therapeutic target for a broad range of pathophysiological conditions including pain, ischemic stroke, depression, and autoimmune diseases such as multiple sclerosis. The only known selective blocker of ASIC1a is π-TRTX-Pc1a (PcTx1), a disulfide-rich 40-residue peptide isolated from spider venom. π-TRTX-Pc1a is an effective analgesic in rodent models of acute pain and it provides neuroprotection in a mouse model of ischemic stroke. Thus, understanding the molecular basis of the π-TRTX-Pc1a–ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system to produce a panel of π-TRTX-Pc1a mutants for probing structure-activity relationships as well as isotopically labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a β-hairpin loop that was revealed to be mobile over a wide range of time scales using molecular dynamics simulations in combination with NMR spin relaxation and relaxation dispersion measurements. The toxin-receptor interaction was modeled by in silico docking of the toxin structure onto a homology model of rat ASIC1a in a restraints-driven approach that was designed to take account of the dynamics of the toxin pharmacophore and the consequent remodeling of side-chain conformations upon receptor binding. The resulting model reveals new insights into the mechanism of action of π-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful π-TRTX-Pc1a mimetics.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Health and Medical Research Council of Australia [Project Grant 511067]; and the Australian Research Council [Discovery Grants DP0878608, DP0987043, DP0879065]. N.J.S. was supported by an Australian Postgraduate Award from the Australian Research Council. M.B. was supported by postdoctoral fellowships from the Swiss National Science Foundation [Fellowships PBBEP3-125613, PA00P3-134167].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.072207.

  • ABBREVIATIONS:

    ASIC
    acid-sensing ion channel
    PcTx1
    Psalmopoeus cambridgei toxin-1 (psalmotoxin-1)
    π-TRTX-Pc1a
    π-theraphotoxin-Pc1a
    MBP
    maltose binding protein
    TEV
    tobacco etch virus
    IPTG
    isopropyl β-d-1-thiogalactopyranoside
    Ni-NTA
    nickel-nitrilotriacetic acid
    HPLC
    high-performance liquid chromatography
    rpHPLC
    reversed-phase high-performance liquid chromatography
    MALDI-TOF
    matrix-assisted laser desorption ionization/time of flight
    MS
    mass spectroscopy
    NUS
    nonuniform sampling
    HSQC
    heteronuclear single quantum correlation
    NOESY
    nuclear Overhauser effect (or enhancement) spectroscopy
    HNHB
    (amide proton)-(nitrogen)-(β-proton) correlation
    NOE
    nuclear Overhauser effect
    3D
    three dimensional
    CPMG
    Carr-Purcell-Meiboom-Gill
    MD
    molecular dynamics
    ECD
    extracellular domain
    TM
    transmembrane
    PDB
    Protein Data Bank
    AIR
    ambiguous interaction restraint
    R1
    longitudinal relaxation rate
    R2
    transverse relaxation rate
    Rex
    chemical/conformational exchange rate constant.

  • Received March 12, 2011.
  • Accepted August 8, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 80 (5)
Molecular Pharmacology
Vol. 80, Issue 5
1 Nov 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
A Dynamic Pharmacophore Drives the Interaction between Psalmotoxin-1 and the Putative Drug Target Acid-Sensing Ion Channel 1a
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Molecular Basis of the π-TRTX-Pc1a-ASIC1a Interaction

Natalie J. Saez, Mehdi Mobli, Michael Bieri, Irène R. Chassagnon, Alpeshkumar K. Malde, Roland Gamsjaeger, Alan E. Mark, Paul R. Gooley, Lachlan D. Rash and Glenn F. King
Molecular Pharmacology November 1, 2011, 80 (5) 796-808; DOI: https://doi.org/10.1124/mol.111.072207

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Molecular Basis of the π-TRTX-Pc1a-ASIC1a Interaction

Natalie J. Saez, Mehdi Mobli, Michael Bieri, Irène R. Chassagnon, Alpeshkumar K. Malde, Roland Gamsjaeger, Alan E. Mark, Paul R. Gooley, Lachlan D. Rash and Glenn F. King
Molecular Pharmacology November 1, 2011, 80 (5) 796-808; DOI: https://doi.org/10.1124/mol.111.072207
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Hexahydroquinoline derivatives activate ADGRG1/GPR56
  • Action of Org 34167 on HCN channels
  • The effects of echinocystic acid on Kv7 channels
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics