EFFECT OF TOLL-LIKE RECEPTOR INHIBITOR IMIQUIMOD ON IL1R1 INTERACTION WITH IL-1RA AND ITS SNP VARIANT-AN IN SILICO APPROACH
Keywords:
Keywords, Interleukin 1 beta, interleukin 1 receptor antagonist, SNP, IL-1RaAbstract
Objective: Interleukin 1 receptor antagonist (IL1Ra) acts as an antagonist to Interleukin 1 beta (IL1β) signalling in maintaining homeostasis. A loss of function due to Single Nucleotide Polymorphism (SNP) occurrence in IL1Ra can lead to dysregulated state as seen in autoimmune disease pathogenesis. The current study aims at achieving conformational stability in the IL1R1-IL1Ra_SNP complex by introducing a ligand into the region apart from the active site of Interleukin 1 receptor type1 (IL1R1).
Methods: Protein-protein docking was performed using ClusPro, for IL1R1 with IL1β, IL1Ra and IL1Ra_SNP variant to study the difference in the interaction between the complexes. A known inhibitor, Imiquimod was docked using Glide, to the Il1R1-IL1Ra_SNP complex using flexible docking and the change in surface energy was calculated.
Results: Binding Interactions show that IL1Ra binds more avidly to IL1R1 than IL1β. Conformational instability was seen in the IL1R1-IL1Ra_SNP complex. The difference in the amino acid interactions between the IL1R1 with IL1Ra and IL1Ra_SNP variant further illustrated the change in binding residues and hydrogen bond formation. Upon docking of an appropriate ligand to the IL1R1-IL1Ra_SNP complex, the conformational stability of the IL1R1-IL1Ra_SNP complex enhanced considerably suggesting a possible mechanism for treating SNP-induced conformational instability.
Conclusion: Toll-like receptors like IL1R1 have many binding pockets apart from its active site. No strategies have yet been reported in targeting them for correcting conformational instability induced by SNP. Through our study, it was observed that the conformational instability of IL1R1-IL1Ra_SNP complex decreased upon introducing an appropriate small molecule.
Keywords: IL1β, IL1R1, IL1Ra, SNP
Downloads
References
Boissier MC, Assier E, Biton J, Denys A, Falgarone G, Bessis N. Regulatory T cells (Treg) in rheumatoid arthritis. Jt Bone Spine 2009;76:10-4.
Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC. A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 2006;203:1685-91.
Subramaniam S, Stansberg C, Cunningham C. The interleukin 1 receptor family. Dev Comp Immunol 2004;28:415-28.
Dinarello CA. The biologic basis for interleukin-1 in disease. Blood 1996;87:2095-147.
Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 1998;16:27-55.
Smith AJ, Keen LJ, Billingham MJ, Perry MJ, Elson CJ, Kirwan JR, et al. Extended haplotypes and linkage disequilibrium in the IL1R1–IL1A–IL1B–IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 2004;5:451-60.
Dunne A, O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci Signal 2003;171:re3.
Dinarello CA. Blocking IL-1 in systemic inflammation. J Exp Med 2005;201:1355-9.
Arend WP. The balance between IL-1 and IL1Ra in disease. Cytokine Growth Factor Rev 2002;13:323-40.
Vigers GP, Anderson LJ, Caffes P, Brandhuber BJ. Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1β. Nature 1997;386:190-4.
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003;423:356-61.
Buchs N, Di Giovine FS, Silvestri T, Vannier E, Duff GW, Miossec P. IL-1B and IL1Ra gene polymorphisms and disease severity in rheumatoid arthritis: interaction with their plasma levels. Genes Immun 2001;2:222-8.
Mantovani A, Locati M, Vecchi A, Sozzani S, Allavena P. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. Trends Immunol 2001;22:328-36.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucleic Acids Res 2000;28:235-42.
Kuntal BK, Aparoy P, Reddanna P. EasyModeller: A graphical interface to the modeller. BMC Res Notes 2010;3:226.
Comeau SR, Gatchell DW, Vajda S, Camacho CJ. ClusPro: a fully automated algorithm for protein–protein docking. Nucleic Acids Res 2004;32:W96-9.
Ramachandran S, Kota P, Ding F, Dokholyan NV. Automated minimization of steric clashes in protein structures. Proteins: Struct Funct Bioinf 2011;79:261-70.
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001;29:308-11.
Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995;8:127-34.
Jayaram B, Liu Y, Beveridge DL. A modification of the generalized Born theory for improved estimates of solvation energies and pK shifts. J Chem Phys 1998;109:1465-71.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004;47:1739-49.
Negi SS, Schein CH, Oezguen N, Power TD, Braun W. InterProSurf: a web server for predicting interacting sites on protein surfaces. Bioinformatics 2007;23:3397-9.
Van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 2009;182:5836-45.
Ozbabacan SE, Gursoy A, Nussinov R, Keskin O. The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer. PLoS Comput Biol 2014;10:e1003470. Doi:10.1371/journal.pcbi.1003470. [Article in Press]
Arend WP, Welgus HG, Thompson R, Eisenberg SP. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 1990;85:1694-7.
Dill KA. Theory for the folding and stability of globular proteins. Biochemistry 1985;24:1501-9.
Zhu S, Paoletti P. Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol 2015;20:14-23.