See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/302458549 Molecular Model of Cytotoxin-1 from Naja mossambica mossambica Venom in Complex with Chymotrypsin Article in Rivista di biologia · December 2015 DOI: 10.1400/240197 CITATIONS READS 2 758 5 authors, including: Aisha Munawar Ashiq Hussain University of Engineering and Technology, Lahore Lahore University of Management Sciences 20 PUBLICATIONS 96 CITATIONS 25 PUBLICATIONS 322 CITATIONS SEE PROFILE SEE PROFILE Patrick Jack Spencer Instituto de Pesquisas Energéticas e Nucleares 63 PUBLICATIONS 690 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Characterization and evaluation of the immune response of the Tetanus toxin submitted to gamma irradiation by Cobalt-60 View project Biotechnology Patents in India - A timeline of 2000 and 2014 View project All content following this page was uploaded by Ashiq Hussain on 12 May 2016. 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Under Italian civil law this publication cannot be reproduced, wholly or in part (included offprints, etc.), in any form (included proofs, etc.), original or derived, or by any means: print, internet (included personal and institutional web sites, academia.edu, etc.), electronic, digital, mechanical, including photocopy, pdf, microfilm, film, scanner or any other medium, without permission in writing from the publisher. ISSN 2282-2593 ISSN ELETTRONICO 1825-6538 CONTENTS Editorial 9 note Armando Bazzani, Dynamical Systems on Graphs: from Random Walks to Transportation Networks 13 articles Pieranna Fietta, Elvira Costa, Giovanni Delsante, Interleukins (ILS), a Fascinating Family of Cytokines. Part II: ILS from IL-20 to IL-38 19 Sumbul Firdaus, Anupam Dhasmana, Shafiul Haque, Snober S Mir, Roshan Jahan, Tasneem Bano, Vandana Srivastava, Saif Khan, Mohtashim Lohani,Interaction Pattern of Fullerenes (C20-C180) and Carbon Nanotubes with Different Forms of DNA: A Computational Biology Approach 41 Yi Fu, Zhiguo Chen, Ji Zhao, Molecular Dynamics Simulation to Elucidate the Thermostability of B Domain in CGTase 57 Valter Lubrano, Elena Venturi, Silvana Balzan, Simona Baldi, An- drea Natali, Impact of Risk Factor for Atherosclerosis on Microvascular En- dothelial Function: an in vitro Study 75 Aisha Munawar, Ahmed Akrem, Ashiq Hussain, Patrick Spencer, Christian Betzel, Molecular Model of Cytotoxin-1 from Naja mossambica mossambica Venom in Complex with Chymotrypsin 89 Sergio Pennazio, The Concept of Plant Life: the Dawn 101 Franco Spirito, The Establishment of Prezygotic Reproductive Isolation in Some Simple Models 121 Instructions for Authors 147 MOLECULAR MODEL OF CYTOTOXIN-1 FROM NAJA MOSSAMBICA MOSSAMBICA VENOM IN COMPLEX WITH CHYMOTRYPSIN Aisha Munawar1 · Ahmed Akrem2 · Ashiq Hussain3 Patrick Spencer4 · Christian Betzel5 1. Department of Chemistry, University of Engineering and Technology, G. T. Road, PK-54890 Lahore (Pakistan) 2. Botany Division, Institute of Pure and Applied Biology, Bahauddin Zakariya University, PK-60800 Multan (Pakistan). Email: [email protected] 3. Ashiq Hussain, Max-Planck-Institute for Neurobiology, Am Klopferspitz 18, D-82152, Martinsried (Germany). Email: [email protected] 4. Biotechnology Centre, Institute of Nuclear Energy Research, Linnaeus Prestes Avenue, 2242 São Paulo (Brazil). E-mail: [email protected] 5. University of Hamburg, Department of Chemistry, Laboratory for Structural Biology of Infection and Inflammation, /c o DESY. Bldg. 22a, Notkestrasse 85, D-22607 Hamburg (Germany). Email: [email protected] Corresponding author: Aisha Munawar. E-mail: [email protected] Contents: 1. Introduction. 2. Methods. 3. Results. 4. Discussion. 5. Conclusion. Keywords: Antitumor activity, Chymotrypsin, Cytotoxin-1, Naja mossambica mossambica, 20S Proteasome. Abstract: Snake venom is a myriad of biologi- pared by the online server ClusPro.Analysis of the cally active proteins and peptides. Three finger molecular model shows that Cytotoxin-1 (P01467) toxins are highly conserved in their molecular binds to chymotrypsin through its loop I located structure, but interestingly possess diverse biolog- near the N-terminus. The concave side of loop I of ical functions. During the course of evolution the the toxin fits well in the substrate binding pocket introduction of subtle mutations in loop regions of the protease. We propose Phe10 as the dedicat- and slight variations in the three dimensional ed P1 site of the ligand. Being a potent inhibitor structure, has resulted in their functional versa- of the 20S proteasome, cytotoxin-1 (P01467) can tility. Cytotoxin-1 (UniProt ID: P01467), isolated serve as a potential antitumor agent. Already from Naja mossambica mossambica, showed the snake venom cytotoxins have been investigated potential to inhibit chymotrypsin and the chy- for their ability as an anticancer agent. The mo- motryptic activity of the 20S proteasome. In the lecular model of cytotoxin-1 in complex with chy- present work we describe a molecular model of cy- motrypsin provides important information to- totoxin-1 in complex with chymotrypsin, pre- wards understanding the complex formation. 1. Introduction nake venom is a complex mixture of biologically active proteins and peptides. S Among the non-enzymatic components of the snake venom, three finger tox- 90 a. munawar · a. akrem · a. hussain · p. spencer · c. betzel ins belong to the well characterized polypeptides. There are two main types of three finger toxins, neurotoxins and cytotoxins, particularly found in elapid venoms [1]. Apart from that they have also been reported to be present in viperid venoms [2]. These two toxins are structurally similar, but differ significantly in their func- tions [3, 4], leading to structure-function complexities. The dedicated receptors for neurotoxins have been deorphanized e.g., nicotinic acetylcholine receptors [5]. The neurotoxins specifically antagonize these receptors, inhibiting the propagation of neurotransmission across the neuromuscular junction [5, 6]. On the other hand, snake venom cytotoxins (CTs) do not have specific receptors, but rather form ion channels in the cell membrane [4]. These cells, including certain type of tumour cells, may undergo necrosis, in which they lose membrane integrity and rapidly die as a result of cell lysis [7, 8]. Studies have shown that cytotoxins also manifest com- plex activities within the cell like interaction with intracellular organelles e.g., mi- tochondrial lysosomes [9, 10]. Cytotoxins from Naja atra and Naja kaouthia have been reported to inhibit the protein kinase C and this activity is considered of much importance to stop the proliferation of several cancer cell types [11-13]. The cyto- toxic and haemophilic properties of CTs help in cell membrane diffusion. Numer- ous studies have been performed to delineate the molecular mechanism involving the CTs binding with biological membranes [9]. Cytotoxins have been classified in- to two types, P-type and S-type [14]. The P-type CTs are classified on the basis of the Pro-31 residue and S-type is based on the S-32 residue. The P-type CTs bind to the membrane through all three loops and have haemolytic activity, while the S- type CTs bind to the membrane through only one of the three loops and show high- er cytolytic activity