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ISSN (Print): 2211-5501
ISSN (Online): 2211-551X

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Research Article

Prediction of Secondary and Tertiary Structure and Docking of Rb1WT And Rb1R661W Proteins

Author(s): Aimen Sajid, Muhammad Shaoor Saeed, Rabbiah Manzoor Malik*, Sahar Fazal, Shaukat Malik and Mohammad Amjad Kamal

Volume 11, Issue 1, 2022

Published on: 08 March, 2022

Page: [71 - 85] Pages: 15

DOI: 10.2174/2211550111666220127100203

Price: $65

Abstract

Background: Retinoblastoma, a malignancy occurring in the juvenile cells of the retina, is responsible for light detection. It is one of the most emerging ra re childhood and infant cancer. It is initiated by the mutation in Rb1, a first tumor suppressor gene located on chromosome 13q14. Rb1 protein is responsible for cell cycle regulation.

Methods: In our study, secondary and 3D-Structural predictions of Rb1WT and Rb1R661W were made by comparative or homology modeling to find any structural change leading to the disruption in its further interactions. Quality assurance of the structures was done by Ramachandran Plot for a stable structure. Both the proteins were then applied by docking process with proteins of interest.

Results: Secondary structure showed a number of mutations in helixes, β-Hairpins of Rb1R661W. The major change was the loss of β-Hairpin loop, extension and shortening of helixes. 3D comparison structure showed a change in the groove of Rb1R661W. Docking results, unlike RB1 WT, had different and no interactions with some of the proteins of interest. This mutation in Rb1 protein had a deleterious effect on the protein functionality.

Conclusion: This study will help to design the appropriate therapy and also understand the mechanism of disease of retinoblastoma, for researchers and pharmaceuticals.

Keywords: Retinoblastoma, cancer, Rb protein, Rb1WT, Rb1R661W, CDK’s family, E2F family, docking.

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[1]
Fabian ID, Sagoo MS. Understanding retinoblastoma: epidemiology and genetics. Community Eye Health 2018; 31(101): 7.
[PMID: 29915458]
[2]
Stacey AW, Clarke B, Moraitis C, et al. The incidence of binocular visual impairment and blindness in children with bilateral retinoblastoma. Ocul Oncol Pathol 2019; 5(1): 1-7.
[http://dx.doi.org/10.1159/000489313] [PMID: 30675470]
[3]
DerKinderen DJ, Koten JW, Van Romunde LK, et al. Early diagnosis of bilateral retinoblastoma reduces death and blindness. Int J Cancer 1989; 44(1): 35-9.
[http://dx.doi.org/10.1002/ijc.2910440107] [PMID: 2744895]
[4]
Khan AA, Sarwar S, Sadiq MAA, Ahmad I, Tariq N, Sibghat-Ul-Noor . Analysis of orbital malignancies presenting in a tertiary care hospital in Pakistan. Pak J Med Sci 2017; 33(1): 70-4.
[http://dx.doi.org/10.12669/pjms.331.12073] [PMID: 28367175]
[5]
Yun J, Li Y, Xu CT, Pan BR. Epidemiology and Rb1 gene of retinoblastoma. Int J Ophthalmol 2011; 4(1): 103-9.
[http://dx.doi.org/10.3980/j.issn.2222-3959.2011.01.24] [PMID: 22553621]
[6]
Wheeler DL, Church DM, Federhen S, et al. Database resources of the national center for biotechnology. Nucleic Acids Res 2003; 31(1): 28-33.
[http://dx.doi.org/10.1093/nar/gkg033] [PMID: 12519941]
[7]
Mcevoy JD, Dyer MA, Chase C. HHS Public Access 2017; 20(901): 217-25.
[8]
Lohmann DR, Brandt B, Höpping W, Passarge E, Horsthemke B. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Hum Genet 1994; 94(4): 349-54.
[http://dx.doi.org/10.1007/BF00201591] [PMID: 7927327]
[9]
Berry JL, Jubran R, Kim JW, et al. Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer 2013; 60(4): 688-93.
[http://dx.doi.org/10.1002/pbc.24303] [PMID: 22997170]
[10]
Kalsoom S, Ramzan K, Tahir HI, Awan AR, Anjum AA, Wasim M. In silico analysis of missense substitutions in RB1 gene and their effect on metabolic pathways. Pak J Zool 2016; 48(3): 639-44.
[11]
Westbrook J, Feng Z, Chen L, Yang H, Berman HM. The Protein Data Bank and structural genomics. Nucleic Acids Res 2003; 31(1): 489-91.
[http://dx.doi.org/10.1093/nar/gkg068] [PMID: 12520059]
[12]
Jacobson M, Sali A. Comparative protein structure modeling and its applications to drug discovery. Annu Rep Med Chem 2004; 39(04): 259-76.
[http://dx.doi.org/10.1016/S0065-7743(04)39020-2]
[13]
Laskowski RA, James D, Thornton JM. ProFunc: A server for predicting protein function from 3D structure. Nucleic Acids Research 2005; 33(suppl_2): W89-93.
[http://dx.doi.org/10.1093/nar/gki414]
[14]
Rose PW, Chunxiao Bi, Wolfgang F, et al. The RCSB Protein Data Bank: new resources for research and education. Nucleic Acids Res 2013; 41(Database issue): D475-82.
[15]
Selwyne RA, Kholmurodov KT, Koltovaya NA. Homology modelling and molecular dynamics of cyclin-dependent protein kinases. IT Real World Probl 2011; 1-72.
[16]
Eswar N, John B, Mirkovic N, et al. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res 2003; 31(13): 3375-80.
[http://dx.doi.org/10.1093/nar/gkg543] [PMID: 12824331]
[17]
Khan MS, Fazal S. Advanced modelling and functional characterization of B2 Bradykinin Receptor. Int J Bioautomation 2015; 19(2): 123-34.
[18]
von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: A database of predicted functional associations between proteins. Nucleic Acids Res 2003; 31(1): 258-61.
[http://dx.doi.org/10.1093/nar/gkg034] [PMID: 12519996]
[19]
Szklarczyk D, Morris JH, Cook H, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 2017; 45(D1): D362-8.
[http://dx.doi.org/10.1093/nar/gkw937] [PMID: 27924014]
[20]
Elokely KM, Doerksen RJ. Docking challenge: protein sampling and molecular docking performance. J Chem Inf Model 2013; 53(8): 1934-45.
[http://dx.doi.org/10.1021/ci400040d] [PMID: 23530568]
[21]
Duhovny D, Nussinov R, Wolfson HJ. Efficient unbound docking of rigid molecules. Lect Notes Comput Sci 2002; 2452: 185-200.
[http://dx.doi.org/10.1007/3-540-45784-4_14]
[22]
Mashiach E, Schneidman-Duhovny D, Andrusier N, Nussinov R, Wolfson H J. FireDock: A web server for fast interaction refinement in molecular docking. Nucleic Acids Res 36(Web Server issue): W229-32.2008;
[http://dx.doi.org/10.1093/nar/gkn186]
[23]
Leone G, Nuckolls F, Ishida S, et al. Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins. Mol Cell Biol 2000; 20(10): 3626-32.
[http://dx.doi.org/10.1128/MCB.20.10.3626-3632.2000] [PMID: 10779352]
[24]
Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 2008; 8(9): 671-82.
[http://dx.doi.org/10.1038/nrc2399] [PMID: 18650841]
[25]
Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 2015; 16(1): 25-35.
[http://dx.doi.org/10.1016/S1470-2045(14)71159-3] [PMID: 25524798]
[26]
Konecny GE, Winterhoff B, Kolarova T, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 2011; 17(6): 1591-602.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2307] [PMID: 21278246]
[27]
Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 2016; 76(8): 2301-13.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0728] [PMID: 27020857]
[28]
Taylor-Harding B, Aspuria PJ, Agadjanian H, et al. Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS. Oncotarget 2015; 6(2): 696-714.
[http://dx.doi.org/10.18632/oncotarget.2673] [PMID: 25557169]
[29]
Jansen VM, Bhola NE, Bauer JA, et al. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer. Cancer Res 2017; 77(9): 2488-99. [Erratum in: Cancer Res. 2019 Feb 15;79]. [4]. [:874. PMID: 28249908; PMCID: PMC5421398].
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2653] [PMID: 28249908]
[30]
Dai M, Zhang C, Ali A, et al. CDK4 regulates cancer stemness and is a novel therapeutic target for triple-negative breast cancer. Sci Rep 2016; 6(March): 35383.
[http://dx.doi.org/10.1038/srep35383] [PMID: 27759034]
[31]
Aaltonen K, Amini RM, Landberg G, et al. Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer. Breast Cancer Res Treat 2009; 113(1): 75-82.
[http://dx.doi.org/10.1007/s10549-008-9908-5] [PMID: 18240019]
[32]
Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev 2016; 45: 129-38.
[http://dx.doi.org/10.1016/j.ctrv.2016.03.002] [PMID: 27017286]
[33]
Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999; 98(6): 859-69.
[http://dx.doi.org/10.1016/S0092-8674(00)81519-6] [PMID: 10499802]
[34]
Leone G, DeGregori J, Yan Z, et al. E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. Genes Dev 1998; 12(14): 2120-30.
[http://dx.doi.org/10.1101/gad.12.14.2120] [PMID: 9679057]
[35]
Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA. E2f3 is critical for normal cellular proliferation. Genes Dev 2000; 14(6): 690-703.
[http://dx.doi.org/10.1101/gad.14.6.690] [PMID: 10733529]
[36]
Taubert S, Gorrini C, Frank SR, et al. E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol Cell Biol 2004; 24(10): 4546-56.
[http://dx.doi.org/10.1128/MCB.24.10.4546-4556.2004] [PMID: 15121871]
[37]
Lang SE, McMahon SB, Cole MD, Hearing P. E2F transcriptional activation requires TRRAP and GCN5 cofactors. J Biol Chem 2001; 276(35): 32627-34.
[http://dx.doi.org/10.1074/jbc.M102067200] [PMID: 11418595]
[38]
Zhang L, Wang C. F-box protein Skp2: A novel transcriptional target of E2F. Oncogene 2006; 25(18): 2615-27.
[http://dx.doi.org/10.1038/sj.onc.1209286] [PMID: 16331253]
[39]
Yung Y, Walker JL, Roberts JM, Assoian RK. A Skp2 autoinduction loop and restriction point control. J Cell Biol 2007; 178(5): 741-7.
[http://dx.doi.org/10.1083/jcb.200703034] [PMID: 17724117]
[40]
Binné UK, Classon MK, Dick FA, et al. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 2007; 9(2): 225-32.
[http://dx.doi.org/10.1038/ncb1532] [PMID: 17187060]
[41]
Lu Z, Bauzon F, Fu H, et al. Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity. Nat Commun 2014; 5: 3463.
[http://dx.doi.org/10.1038/ncomms4463] [PMID: 24632684]
[42]
Ji P, Jiang H, Rekhtman K, et al. An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell 2004; 16(1): 47-58.
[http://dx.doi.org/10.1016/j.molcel.2004.09.029] [PMID: 15469821]
[43]
Martín A, Odajima J, Hunt SL, et al. Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27Kip1 and p21Cip1. Cancer Cell 2005; 7(6): 591-8.
[http://dx.doi.org/10.1016/j.ccr.2005.05.006]
[44]
Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell 1999; 97(4): 431-4.
[http://dx.doi.org/10.1016/S0092-8674(00)80753-9] [PMID: 10338207]
[45]
Sutterlüty H, Chatelain E, Marti A, et al. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1999; 1(4): 207-14.
[http://dx.doi.org/10.1038/12027] [PMID: 10559918]
[46]
Jun L, Frints S, Duhamel H, et al. NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation. Curr Biol 2001; 11(18): 1381-91.
[http://dx.doi.org/10.1016/S0960-9822(01)00419-5] [PMID: 11566096]
[47]
Li D, Jin T, Gazgalis D, Cui M, Logothetis DE. On the mechanism of GIRK2 channel gating by phosphatidylinositol bisphosphate, sodium, and the Gβγ dimer. J Biol Chem 2019; 294(49): 18934-48.
[http://dx.doi.org/10.1074/jbc.RA119.010047] [PMID: 31659119]
[48]
Nakayama K, Nagahama H, Minamishima YA, et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J 2000; 19(9): 2069-81.
[http://dx.doi.org/10.1093/emboj/19.9.2069] [PMID: 10790373]
[49]
Gstaiger M, Jordan R, Lim M, et al. Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci USA 2001; 98(9): 5043-8.
[http://dx.doi.org/10.1073/pnas.081474898] [PMID: 11309491]
[50]
Etemadmoghadam D, Au-Yeung G, Wall M, et al. Resistance to CDK2 inhibitors is associated with selection of polyploid cells in CCNE1-amplified ovarian cancer. Clin Cancer Res 2013; 19(21): 5960-71.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1337] [PMID: 24004674]
[51]
Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review. Int J Cancer 2019; 145(5): 1179-88.
[http://dx.doi.org/10.1002/ijc.32020] [PMID: 30478914]
[52]
Zhao J, Speel EJM, Muletta-Feurer S, et al. Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis. Am J Pathol 1999; 155(4): 1039-45.
[http://dx.doi.org/10.1016/S0002-9440(10)65205-4] [PMID: 10514385]
[53]
Nurse P. Ordering S phase and M phase in the cell cycle. Cell 1994; 79(4): 547-50.
[http://dx.doi.org/10.1016/0092-8674(94)90539-8] [PMID: 7954820]
[54]
Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW, Jansen-Dürr P. Inactivation of the CDK inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene 1996; 13(11): 2323-30.
[55]
Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer 2002; 2(5): 331-41.
[http://dx.doi.org/10.1038/nrc795] [PMID: 12044009]
[56]
Ashkenazi R, Gentry SN, Jackson TL. Pathways to tumorigenesis-modeling mutation acquisition in stem cells and their progeny. Neoplasia 2008; 10(11): 1170-82.
[http://dx.doi.org/10.1593/neo.08572] [PMID: 18953426]
[57]
Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002; 2(2): 103-12.
[http://dx.doi.org/10.1016/S1535-6108(02)00102-2] [PMID: 12204530]
[58]
Chau BN, Wang JYJ. Coordinated regulation of life and death by RB. Nat Rev Cancer 2003; 3(2): 130-8.
[http://dx.doi.org/10.1038/nrc993] [PMID: 12563312]
[59]
Vogelstein B, Lane D, Levine AJ. Surfing the p53 network : Article : Nature. Nature 2000; 408(6810): 307-10.http://www.nature.com/nature/journal/v408/n6810/full/408307a0.html#B41
[60]
Prives C, Hall PA. The p53 pathway. J Pathol 1999; 187(1): 112-26.
[http://dx.doi.org/10.1002/(SICI)1096-9896(199901)187:1<112::AID-PATH250>3.0.CO;2-3] [PMID: 10341712]
[61]
Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420(1): 25-7.
[http://dx.doi.org/10.1016/S0014-5793(97)01480-4] [PMID: 9450543]
[62]
Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res 1998; 26(15): 3453-9.
[http://dx.doi.org/10.1093/nar/26.15.3453]
[63]
Zhou J, Shi J, Fu X, et al. Linc00441 interacts with DNMT1 to regulate RB1 gene methylation and expression in gastric cancer. Oncotarget 2018; 9(101): 37471-9.
[http://dx.doi.org/10.18632/oncotarget.23928] [PMID: 30680063]
[64]
Shamma A, Suzuki M, Hayashi N, et al. ATM mediates pRB function to control DNMT1 protein stability and DNA methylation. Mol Cell Biol 2013; 33(16): 3113-24.
[http://dx.doi.org/10.1128/MCB.01597-12] [PMID: 23754744]

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