6ats

Exploring Cystine Dense Peptide Space to Open a Unique Molecular ToolboxExploring Cystine Dense Peptide Space to Open a Unique Molecular Toolbox

Structural highlights

6ats is a 1 chain structure with sequence from Chersonesometrus fulvipes. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KKX11_CHEFU Shows weak blocking activity on voltage-gated potassium channels Kv10.1/KCNH1/EAG1 (IC(50)=26 uM), Kv1.2/KCNA2 (Kd=150 uM), Kv1.3/KCNA3 (Kd=40 uM), Kv1.6/KCNA3 (16.6% inhibition at 40 uM toxin) (PubMed:12034709, PubMed:23726856, PubMed:27578329). The block is dose-dependent, voltage-independent, and reversible (PubMed:12034709). Also shows a weak inhibitory activity on the plant pathogen F.culmorum growth (IC(50)=18.8-37.7 uM) (PubMed:27578329).^[1] ^[2] ^[3]

Publication Abstract from PubMed

Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high-throughput expression, screening and large-scale production of these peptides: 46 were successfully produced in multimilligram quantities, and >600 more were deemed expressible through stringent screening criteria. Many showed extreme resistance to temperature, proteolysis and/or reduction, and all displayed inhibitory activity against at least 1 of 20 ion channels tested, thus confirming their biological functionality. Crystal structures of 12 confirmed proper cystine topology and the utility of crystallography to study these molecules but also highlighted the need for rational classification. Previous categorization attempts have focused on limited subsets featuring distinct motifs. Here we present a global definition, classification and analysis of >700 structures of cystine-dense peptides, providing a unifying framework for these molecules.

Screening, large-scale production and structure-based classification of cystine-dense peptides.,Correnti CE, Gewe MM, Mehlin C, Bandaranayake AD, Johnsen WA, Rupert PB, Brusniak MY, Clarke M, Burke SE, De Van Der Schueren W, Pilat K, Turnbaugh SM, May D, Watson A, Chan MK, Bahl CD, Olson JM, Strong RK Nat Struct Mol Biol. 2018 Mar;25(3):270-278. doi: 10.1038/s41594-018-0033-9. Epub, 2018 Feb 26. PMID:29483648^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Srinivasan KN, Sivaraja V, Huys I, Sasaki T, Cheng B, Kumar TK, Sato K, Tytgat J, Yu C, San BC, Ranganathan S, Bowie HJ, Kini RM, Gopalakrishnakone P. kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity. J Biol Chem. 2002 Aug 16;277(33):30040-7. Epub 2002 May 28. PMID:12034709 doi:10.1074/jbc.M111258200
↑ Peigneur S, Yamaguchi Y, Goto H, Srinivasan KN, Gopalakrishnakone P, Tytgat J, Sato K. Synthesis and characterization of amino acid deletion analogs of κ-hefutoxin 1, a scorpion toxin on potassium channels. Toxicon. 2013 Sep;71:25-30. PMID:23726856 doi:10.1016/j.toxicon.2013.05.010
↑ Moreels L, Peigneur S, Yamaguchi Y, Vriens K, Waelkens E, Zhu S, Thevissen K, Cammue BPA, Sato K, Tytgat J. Expanding the pharmacological profile of κ-hefutoxin 1 and analogues: A focus on the inhibitory effect on the oncogenic channel K(v)10.1. Peptides. 2017 Dec;98:43-50. PMID:27578329 doi:10.1016/j.peptides.2016.08.008
↑ Correnti CE, Gewe MM, Mehlin C, Bandaranayake AD, Johnsen WA, Rupert PB, Brusniak MY, Clarke M, Burke SE, De Van Der Schueren W, Pilat K, Turnbaugh SM, May D, Watson A, Chan MK, Bahl CD, Olson JM, Strong RK. Screening, large-scale production and structure-based classification of cystine-dense peptides. Nat Struct Mol Biol. 2018 Mar;25(3):270-278. doi: 10.1038/s41594-018-0033-9. Epub, 2018 Feb 26. PMID:29483648 doi:http://dx.doi.org/10.1038/s41594-018-0033-9

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Srinivasan KN, Sivaraja V, Huys I, Sasaki T, Cheng B, Kumar TK, Sato K, Tytgat J, Yu C, San BC, Ranganathan S, Bowie HJ, Kini RM, Gopalakrishnakone P. kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity. J Biol Chem. 2002 Aug 16;277(33):30040-7. Epub 2002 May 28. PMID:12034709 doi:10.1074/jbc.M111258200

[2] Peigneur S, Yamaguchi Y, Goto H, Srinivasan KN, Gopalakrishnakone P, Tytgat J, Sato K. Synthesis and characterization of amino acid deletion analogs of κ-hefutoxin 1, a scorpion toxin on potassium channels. Toxicon. 2013 Sep;71:25-30. PMID:23726856 doi:10.1016/j.toxicon.2013.05.010

[3] Moreels L, Peigneur S, Yamaguchi Y, Vriens K, Waelkens E, Zhu S, Thevissen K, Cammue BPA, Sato K, Tytgat J. Expanding the pharmacological profile of κ-hefutoxin 1 and analogues: A focus on the inhibitory effect on the oncogenic channel K(v)10.1. Peptides. 2017 Dec;98:43-50. PMID:27578329 doi:10.1016/j.peptides.2016.08.008

[4] Correnti CE, Gewe MM, Mehlin C, Bandaranayake AD, Johnsen WA, Rupert PB, Brusniak MY, Clarke M, Burke SE, De Van Der Schueren W, Pilat K, Turnbaugh SM, May D, Watson A, Chan MK, Bahl CD, Olson JM, Strong RK. Screening, large-scale production and structure-based classification of cystine-dense peptides. Nat Struct Mol Biol. 2018 Mar;25(3):270-278. doi: 10.1038/s41594-018-0033-9. Epub, 2018 Feb 26. PMID:29483648 doi:http://dx.doi.org/10.1038/s41594-018-0033-9

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