Computational Protein-Protein Docking Reveals the Therapeutic Potential of Kunitz-type Venom against hKv1.2 Binding Sites

Author(s): Rida Khalid, Nighat Noureen, Mohammad Amjad Kamal, Sidra Batool*.

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 5 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background & Objective: Kunitz-type venoms are bioactive proteins isolated from a wide variety of venomous animals. These venoms are involved in protease inhibitory activity or potassium channel blocking activity. Therefore, they are reported as an important source for lead drug candidates towards protease or channel associated diseases like neurological, metabolic and cardiovascular disorders.

Methods: This study aimed to check the inhibitory action of Kunitz-type venoms against potassium channels using computational tools.

Results: Among potassium channels, Human Voltage-Gated Potassium Channel 1.2 (hKv1.2) was used as a receptor whereas Kunitz-type peptides from the venoms of various species were selected as ligand dataset.

Conclusion: This study helped in finding the binding interface between the receptor and ligand dataset for their potential therapeutic use in treating potassium channelopathies.

Keywords: Kunitz-type venoms, human Kv1.2, docking, CS alpha/beta fold, autoimmune, metabolic.

[1]
Zhao R, Dai H, Qiu S, et al. SdPI, the first functionally characterized kunitz-type trypsin inhibitor from scorpion venom. PLoS One 2011; 6(11)e27548
[2]
Huang Y, Wang Y, Yan R, et al. The role of traditional chinese herbal medicines and bioactive ingredients on ion channels: A brief review and prospect. CNS Neurol Disord Drug Targets 2019; 18(4): 257-65.
[3]
Harvey AL. Twenty years of dendrotoxins. Toxicon J Int Soc Toxinol 2001; 39(1): 15-26.
[4]
Wan H, Lee KS, Kim BY, et al. A spider-derived kunitz-type serine protease inhibitor that acts as a plasmin inhibitor and an elastase inhibitor. PLoS One 2013; 8(1)e53343
[5]
Choo YM, Lee KS, Yoon HJ, et al. Antifibrinolytic role of a bee venom serine protease inhibitor that acts as a plasmin inhibitor. PLoS One 2012; 7(2)e32269
[6]
Masci PP, Whitaker AN, Sparrow LG. Textilinins from Pseudonaja textilis textilis. Characterization of two plasmin inhibitors that reduce bleeding in an animal model. Blood Coagul 2000; 11(4): 385-93.
[7]
Yang W, Feng J, Wang B, et al. BF9, the first functionally characterized snake toxin peptide with Kunitz-type protease and potassium channel inhibiting properties. J Biochem Mol Toxicol 2014; 28(2): 76-83.
[8]
Schweitz H, Bruhn T, Guillemare E. Kalicludines and kaliseptine. Two different classes of sea anemone toxins for voltage sensitive K+ channels. J Biol Chem 1995; 270(42): 25121-6.
[9]
Chen ZY, Hu YT, Yang WS, et al. Hg1, novel peptide inhibitor specific for Kv1.3 channels from first scorpion Kunitz-type potassium channel toxin family. J Biol Chem 2012; 287(17): 13813-21.
[10]
Huang Y, Tao J, Zhao R. Potassium channels and CNS diseases. CNS Neurol Disord Drug Targets 2018; 17(4): 245-7.
[11]
Wulff H, Castle NA, Pardo LA. Voltage-gated Potassium Channels as Therapeutic Drug Targets. Nat Rev Drug Discov 2009; 8(12): 982-1001.
[12]
Purves D, Augustine GJ, Fitzpatrick D, et al. Electrical signals of nerve cells.In: Neuroscience. 2nd Edition. Sunderland, (MA): Sinauer Associates 2001.
[13]
Zang K, Zhang Y, Hu J, Wang Y. The large conductance calcium- and voltage-activated potassium channel (BK) and epilepsy. CNS Neurol Disord Drug Targets 2018; 17(4): 248-54.
[14]
Zhu Y, Zhang S, Feng Y, Xiao Q, Cheng J, Tao J. The yin and yang of BK channels in epilepsy. CNS Neurol Disord Drug Targets 2018; 17(4): 272-9.
[15]
Yang J, Yan X. Oxidation of potassium channels in neurodegenerative diseases: A mini-review. CNS Neurol Disord Drug Targets 2018; 17(4): 267-71.
[16]
Feng X, Zhao Z, Li Q, Tan Z. Lysosomal potassium channels: Potential roles in lysosomal function and neurodegenerative diseases. CNS Neurol Disord Drug Targets 2018; 17(4): 261-6.
[17]
Thangudu RR, Manoharan M, Srinivasan N, Cadet F, Sowdhamini R, Offmann B. Analysis on conservation of disulphide bonds and their structural features in homologous protein domain families. BMC Struct Biol 2008; 26: 8-55.
[18]
Antuch W, Güntert P, Billeter M, Hawthorne T, Grossenbacher H, Wüthrich K. NMR solution structure of the recombinant tick anticoagulant protein (rTAP), a factor Xa inhibitor from the tick Ornithodoros moubata. FEBS Lett 1994; 352(2): 251-7.
[19]
Siddiqi AR, Zaidi ZH, Jörnvall H. Purification and characterization of a Kunitz-type trypsin inhibitor from Leaf-nosed viper venom. FEBS Lett 1991; 294(1-2): 141-3.
[20]
Chand HS, Schmidt AE, Bajaj SP, Kisiel W. Structure-function analysis of the reactive site in the first Kunitz-type domain of human tissue factor pathway inhibitor-2. J Biol Chem 2004; 279(17): 17500-7.
[21]
García-Fernández R, Peigneur S, Pons T. The kunitz-type protein ShPI-1 inhibits serine proteases and voltage-gated potassium channels. Toxins 2016; 8(4): 110.
[22]
Corpet F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res 1988; 16(22): 10881-90.
[23]
Małysiak K, Grzywna ZJ. Electrostatic interactions during Kv1.2 N-type inactivation: Random-walk simulation. Eur Biophys 2009; 38(7): 1003-12.
[24]
Yeheskel A, Haliloglu T, Ben-Tal N. Independent and cooperative motions of the kv1.2 channel: Voltage sensing and gating. Biophys J 2010; 98(10): 2179-88.
[25]
KCNA2 - Potassium voltage-gated channel subfamily a member 2-Homo sapiens (Human) - KCNA2 gene & protein [Internet]. [cited 2016 Dec 13]. Available from:http://www.uniprot.org/ uniprot/P16389
[26]
Morris GM, Huey R, Lindstrom W. Auto Dock4 and Auto DockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[27]
Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995; 8(2): 127-34.
[28]
Pettersen EF, Goddard TD, Huang CC, Couch GS. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004; 25(13): 1605-12.
[29]
Chen R, Chung SH. Structural basis of the selective block of Kv1.2 by maurotoxin from computer simulations. PLoS One 2012; 7(10)e47253
[30]
Khabiri M, Nikouee A, Cwiklik L, Grissmer S, Ettrich R. Charybdotoxin unbinding from the mKv1.3 potassium channel: a combined computational and experimental study. J Phys Chem B 2011; 115(39): 11490-500.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 5
Year: 2019
Page: [382 - 404]
Pages: 23
DOI: 10.2174/1871527318666190319140204
Price: $58

Article Metrics

PDF: 41
HTML: 3
EPUB: 1
PRC: 1