Conkazal-M1 from the MKAVA family of conotoxins: A dual-function protease inhibitor and neuroactive peptide.
Overview
- Department of Biology, Linderstrøm‐Lang Centre for Protein Science University of Copenhagen Copenhagen Denmark
- Department of Biochemistry University of Utah Salt Lake City Utah USA
- Department of Biomedical Sciences University of Copenhagen Denmark
- School of Biological Sciences University of Utah Salt Lake City Utah USA
Abstract
Marine cone snails produce a diverse array of bioactive peptides, known as conotoxins, in their venom. Given their high target potency and specificity, conotoxins are attractive compounds for the development of precision research tools and pharmacological agents. Here, we provide the first experimental characterization of a conotoxin from the MKAVA superfamily, conkazal‐M1, from Conus magus. Using NMR spectroscopy, we show that conkazal‐M1 adopts a fold characteristic of the Kazal‐type protease inhibitor family, featuring a Glu residue at the inhibitory P1 position. Recombinantly expressed conkazal‐M1 inhibits the proteolytic activity of Subtilisin A with an apparent Ki of 1.1 μM. In addition, conkazal‐M1 partially inhibits calcium transients in mouse sensory neurons, suggesting a potential role in modulating ion‐channel activity, as seen for many other toxins. The dual function of conkazal‐M1 in protease inhibition and neuroactivity is analogous to the dual function of several toxins harboring a Kunitz‐type fold. The well‐conserved sequence of the MKAVAs indicates an evolutionary trajectory in which these proteins face an adaptive conflict, where mutations that enhance one activity compromise the other. Collectively, this work provides new structural and functional insights into a previously uncharacterized toxin superfamily in cone snails, illustrates how structural scaffolds can be repurposed for functions that diverge from the original while retaining their overall structure, and expands our understanding of the toxin arsenal available to venomous animals.
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
Code
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Data
Datasets cited
- bioinformatics.org/
firstglance/ — at bioinformatics.org; found in the text, “NMR structure calculations”fgij - bmrb.wisc.edu — at bmrb.wisc.edu; found in the text, “NMR structure calculations”
Data availability statement
The atomic coordinates for conkazal‐M1 are available with the Protein Data Bank under accession number 9SLR and in the Biological Magnetic Resonance Data Bank under ID number 53313.
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 7 keywords, 9 MeSH terms, 4 funders, 72 references.
Cite
This paper
Hackney, C. M., Koch, T. L., Ryding, N. L., Rogalski, A., Chase, K., Giglio, M. L., Espino, S. S., Acyatan, Z. G., Watkins, M., Olivera, B. M., Safavi‐Hemami, H., Teilum, K., & Ellgaard, L. (2026). Conkazal-M1 from the MKAVA family of conotoxins: A dual-function protease inhibitor and neuroactive peptide. Protein science : a publication of the Protein Society, 35(5), e70580. https://
BibTeX
@article{hackney2026conk
author = {Hackney, Celeste M. and Koch, Thomas Lund and Ryding, Nicklas Lund and Rogalski, Aymeric and Chase, Kevin and Giglio, Matías Leonel and Espino, Samuel S. and Acyatan, Zildjian G. and Watkins, Maren and Olivera, Baldomero M. and Safavi‐Hemami, Helena and Teilum, Kaare and Ellgaard, Lars},
title = {{Conkazal-M1 from the MKAVA family of conotoxins: A dual-function protease inhibitor and neuroactive peptide}},
journal = {Protein science : a publication of the Protein Society},
year = {2026},
month = may,
volume = {35},
number = {5},
pages = {e70580},
publisher = {Wiley},
issn = {0961-8368},
doi = {10.1002/
url = {https://
pmid = {42017756},
pmcid = {PMC13101452}
}
RIS
TY - JOUR
AU - Hackney, Celeste M.
AU - Koch, Thomas Lund
AU - Ryding, Nicklas Lund
AU - Rogalski, Aymeric
AU - Chase, Kevin
AU - Giglio, Matías Leonel
AU - Espino, Samuel S.
AU - Acyatan, Zildjian G.
AU - Watkins, Maren
AU - Olivera, Baldomero M.
AU - Safavi‐Hemami, Helena
AU - Teilum, Kaare
AU - Ellgaard, Lars
TI - Conkazal-M1 from the MKAVA family of conotoxins: A dual-function protease inhibitor and neuroactive peptide
T2 - Protein science : a publication of the Protein Society
J2 - Protein Sci
PY - 2026
DA - 2026/
VL - 35
IS - 5
SP - e70580
SN - 0961-8368
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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