Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1.
Identifieur interne : 000E23 ( PubMed/Checkpoint ); précédent : 000E22; suivant : 000E24Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1.
Auteurs : Sing Yan Er [Australie] ; Ben Cristofori-Armstrong [Australie] ; Pierre Escoubas [France] ; Lachlan D. Rash [Australie]Source :
- Neuropharmacology [ 1873-7064 ] ; 2017.
Abstract
Acute pharmacological inhibition of acid-sensing ion channel 1a (ASIC1a) is efficacious in rodent models in alleviating symptoms of neurological diseases such as stroke and multiple sclerosis. Thus, ASIC1a is a promising therapeutic target and selective ligands that modulate it are invaluable research tools and potential therapeutic leads. Spider venoms have provided an abundance of voltage-gated ion channel modulators, however, only one ASIC modulator (PcTx1) has so far been isolated from this source. Here we report the discovery, characterization, and chemical stability of a second spider venom peptide that potently modulates ASIC1a and ASIC1b, and investigate the molecular basis for its subtype selectivity. π-TRTX-Hm3a (Hm3a) is a 37-amino acid peptide isolated from Togo starburst tarantula (Heteroscodra maculata) venom with five amino acid substitutions compared to PcTx1, and is also three residues shorter at the C-terminus. Hm3a pH-dependently inhibited ASIC1a with an IC50 of 1-2 nM and potentiated ASIC1b with an EC50 of 46.5 nM, similar to PcTx1. Using ASIC1a to ASIC1b point mutants in rat ASIC1a revealed that Glu177 and Arg175 in the palm region opposite α-helix 5 play an important role in the Hm3a-ASIC1 interaction and contribute to the subtype-dependent effects of the peptide. Despite its high sequence similarity with PcTx1, Hm3a showed higher levels of stability over 48 h. Overall, Hm3a represents a potent, highly stable tool for the study of ASICs and will be particularly useful when stability in biological fluids is required, for example in long term in vitro cell-based assays and in vivo experiments.
DOI: 10.1016/j.neuropharm.2017.03.020
PubMed: 28327374
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Rash</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: l.rash@uq.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072</wicri:regionArea><wicri:noRegion>QLD 4072</wicri:noRegion></affiliation></author></analytic><series><title level="j">Neuropharmacology</title><idno type="eISSN">1873-7064</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Acute pharmacological inhibition of acid-sensing ion channel 1a (ASIC1a) is efficacious in rodent models in alleviating symptoms of neurological diseases such as stroke and multiple sclerosis. Thus, ASIC1a is a promising therapeutic target and selective ligands that modulate it are invaluable research tools and potential therapeutic leads. Spider venoms have provided an abundance of voltage-gated ion channel modulators, however, only one ASIC modulator (PcTx1) has so far been isolated from this source. Here we report the discovery, characterization, and chemical stability of a second spider venom peptide that potently modulates ASIC1a and ASIC1b, and investigate the molecular basis for its subtype selectivity. π-TRTX-Hm3a (Hm3a) is a 37-amino acid peptide isolated from Togo starburst tarantula (Heteroscodra maculata) venom with five amino acid substitutions compared to PcTx1, and is also three residues shorter at the C-terminus. Hm3a pH-dependently inhibited ASIC1a with an IC50 of 1-2 nM and potentiated ASIC1b with an EC50 of 46.5 nM, similar to PcTx1. Using ASIC1a to ASIC1b point mutants in rat ASIC1a revealed that Glu177 and Arg175 in the palm region opposite α-helix 5 play an important role in the Hm3a-ASIC1 interaction and contribute to the subtype-dependent effects of the peptide. Despite its high sequence similarity with PcTx1, Hm3a showed higher levels of stability over 48 h. Overall, Hm3a represents a potent, highly stable tool for the study of ASICs and will be particularly useful when stability in biological fluids is required, for example in long term in vitro cell-based assays and in vivo experiments.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">28327374</PMID><DateCreated><Year>2017</Year><Month>03</Month><Day>22</Day></DateCreated><DateRevised><Year>2017</Year><Month>03</Month><Day>31</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1873-7064</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2017</Year><Month>Mar</Month><Day>19</Day></PubDate></JournalIssue><Title>Neuropharmacology</Title><ISOAbbreviation>Neuropharmacology</ISOAbbreviation></Journal><ArticleTitle>Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">S0028-3908(17)30112-0</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.neuropharm.2017.03.020</ELocationID><Abstract><AbstractText>Acute pharmacological inhibition of acid-sensing ion channel 1a (ASIC1a) is efficacious in rodent models in alleviating symptoms of neurological diseases such as stroke and multiple sclerosis. Thus, ASIC1a is a promising therapeutic target and selective ligands that modulate it are invaluable research tools and potential therapeutic leads. Spider venoms have provided an abundance of voltage-gated ion channel modulators, however, only one ASIC modulator (PcTx1) has so far been isolated from this source. Here we report the discovery, characterization, and chemical stability of a second spider venom peptide that potently modulates ASIC1a and ASIC1b, and investigate the molecular basis for its subtype selectivity. π-TRTX-Hm3a (Hm3a) is a 37-amino acid peptide isolated from Togo starburst tarantula (Heteroscodra maculata) venom with five amino acid substitutions compared to PcTx1, and is also three residues shorter at the C-terminus. Hm3a pH-dependently inhibited ASIC1a with an IC50 of 1-2 nM and potentiated ASIC1b with an EC50 of 46.5 nM, similar to PcTx1. Using ASIC1a to ASIC1b point mutants in rat ASIC1a revealed that Glu177 and Arg175 in the palm region opposite α-helix 5 play an important role in the Hm3a-ASIC1 interaction and contribute to the subtype-dependent effects of the peptide. Despite its high sequence similarity with PcTx1, Hm3a showed higher levels of stability over 48 h. Overall, Hm3a represents a potent, highly stable tool for the study of ASICs and will be particularly useful when stability in biological fluids is required, for example in long term in vitro cell-based assays and in vivo experiments.</AbstractText><CopyrightInformation>Copyright © 2017 Elsevier Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Er</LastName><ForeName>Sing Yan</ForeName><Initials>SY</Initials><AffiliationInfo><Affiliation>Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cristofori-Armstrong</LastName><ForeName>Ben</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Escoubas</LastName><ForeName>Pierre</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>VenomeTech, 473 Route des Dolines, Villa 3, 06560 Valbonne, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rash</LastName><ForeName>Lachlan D</ForeName><Initials>LD</Initials><AffiliationInfo><Affiliation>Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: l.rash@uq.edu.au.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>03</Month><Day>19</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Neuropharmacology</MedlineTA><NlmUniqueID>0236217</NlmUniqueID><ISSNLinking>0028-3908</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Acid-sensing ion channel 1</Keyword><Keyword MajorTopicYN="N">Hm3a</Keyword><Keyword MajorTopicYN="N">Peptide</Keyword><Keyword MajorTopicYN="N">Peptide stability</Keyword><Keyword MajorTopicYN="N">Structure-activity relationship</Keyword><Keyword MajorTopicYN="N">Venom</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>01</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2017</Year><Month>03</Month><Day>05</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>03</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>3</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>3</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>3</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28327374</ArticleId><ArticleId IdType="pii">S0028-3908(17)30112-0</ArticleId><ArticleId IdType="doi">10.1016/j.neuropharm.2017.03.020</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Australie</li><li>France</li></country></list><tree><country name="Australie"><noRegion><name sortKey="Er, Sing Yan" sort="Er, Sing Yan" uniqKey="Er S" first="Sing Yan" last="Er">Sing Yan Er</name></noRegion><name sortKey="Cristofori Armstrong, Ben" sort="Cristofori Armstrong, Ben" uniqKey="Cristofori Armstrong B" first="Ben" last="Cristofori-Armstrong">Ben Cristofori-Armstrong</name><name sortKey="Rash, Lachlan D" sort="Rash, Lachlan D" uniqKey="Rash L" first="Lachlan D" last="Rash">Lachlan D. Rash</name></country><country name="France"><noRegion><name sortKey="Escoubas, Pierre" sort="Escoubas, Pierre" uniqKey="Escoubas P" first="Pierre" last="Escoubas">Pierre Escoubas</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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