Computational Modeling of IN-CTD/TAR Complex to Elucidate Additional Strategies to Inhibit HIV-1 Replication

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2022 Dec 19

PMID 36534283

Authors

Liming Qiu

Savita Bhutoria

Ganjam V Kalpana

Xiaoqin Zou

Affiliations

Soon will be listed here.

Abstract

HIV-1 integrase (IN) is a key enzyme that is essential for mediating the insertion of retroviral DNA into the host chromosome. IN also exhibits additional functions which are not fully elucidated, including its ability to bind to viral genomic RNA. Lack of binding of IN to RNA within the virions has been shown to be associated with production of morphologically defective virus particles. However, the exact structure of HIV-1 IN bound to RNA is not known. Based on the studies that C-terminal domain (CTD) of IN binds to TAR RNA region and based on the observation that TAR and the host factor INI1 binding to IN-CTD are identical, we computationally modelled the IN-CTD/TAR complex structure. Computational modeling of nucleic acid binding to proteins is a valuable method to understand the macromolecular interaction when experimental methods of solving the complex structures are not feasible. The current model of the IN-CTD/TAR complex may facilitate further understanding of this interaction and may lead to therapeutic targeting of IN-CTD/RNA interactions to inhibit HIV-1 replication.

Citing Articles

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PMID: 39291012 PMC: 11403752. DOI: 10.1021/acsmedchemlett.4c00268.

References

Xu X, Qiu L, Yan C, Ma Z, Grinter S, Zou X . Performance of MDockPP in CAPRI rounds 28-29 and 31-35 including the prediction of water-mediated interactions. Proteins. 2016; 85(3):424-434. PMC: 5313341. DOI: 10.1002/prot.25203. View

Engelman A, Cherepanov P . The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog. 2008; 4(3):e1000046. PMC: 2275779. DOI: 10.1371/journal.ppat.1000046. View

Huang S, Zou X . A knowledge-based scoring function for protein-RNA interactions derived from a statistical mechanics-based iterative method. Nucleic Acids Res. 2014; 42(7):e55. PMC: 3985650. DOI: 10.1093/nar/gku077. View

Kalpana G, Marmon S, Wang W, Crabtree G, Goff S . Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science. 1994; 266(5193):2002-6. DOI: 10.1126/science.7801128. View

Dixit U, Bhutoria S, Wu X, Qiu L, Spira M, Mathew S . INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication. Nat Commun. 2021; 12(1):2743. PMC: 8115288. DOI: 10.1038/s41467-021-22733-9. View

Chen R, Li L, Weng Z . ZDOCK: an initial-stage protein-docking algorithm. Proteins. 2003; 52(1):80-7. DOI: 10.1002/prot.10389. View

Elliott J, Eschbach J, Koneru P, Li W, Puray-Chavez M, Townsend D . Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. Elife. 2020; 9. PMC: 7671690. DOI: 10.7554/eLife.54311. View

Chen R, Weng Z . A novel shape complementarity scoring function for protein-protein docking. Proteins. 2003; 51(3):397-408. DOI: 10.1002/prot.10334. View

Kim D, Chivian D, Baker D . Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res. 2004; 32(Web Server issue):W526-31. PMC: 441606. DOI: 10.1093/nar/gkh468. View

10.

Engelman A, Kvaratskhelia M . Multimodal Functionalities of HIV-1 Integrase. Viruses. 2022; 14(5). PMC: 9144474. DOI: 10.3390/v14050926. View

11.

Katchalski-Katzir E, Shariv I, Eisenstein M, Friesem A, Aflalo C, Vakser I . Molecular surface recognition: determination of geometric fit between proteins and their ligands by correlation techniques. Proc Natl Acad Sci U S A. 1992; 89(6):2195-9. PMC: 48623. DOI: 10.1073/pnas.89.6.2195. View

12.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

13.

Duan R, Qiu L, Xu X, Ma Z, Merideth B, Shyu C . Performance of human and server prediction in CAPRI rounds 38-45. Proteins. 2020; 88(8):1110-1120. PMC: 7423244. DOI: 10.1002/prot.25956. View

14.

Mathew S, Nguyen M, Wu X, Pal A, Shah V, Prasad V . INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo. Retrovirology. 2013; 10:66. PMC: 3708822. DOI: 10.1186/1742-4690-10-66. View

15.

Pau A, George J . Antiretroviral therapy: current drugs. Infect Dis Clin North Am. 2014; 28(3):371-402. PMC: 4143801. DOI: 10.1016/j.idc.2014.06.001. View

16.

Kleinpeter A, Freed E . HIV-1 Maturation: Lessons Learned from Inhibitors. Viruses. 2020; 12(9). PMC: 7552077. DOI: 10.3390/v12090940. View

17.

Huang S, Zou X . An iterative knowledge-based scoring function for protein-protein recognition. Proteins. 2008; 72(2):557-79. DOI: 10.1002/prot.21949. View

18.

Fontana J, Jurado K, Cheng N, Ly N, Fuchs J, Gorelick R . Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation. J Virol. 2015; 89(19):9765-80. PMC: 4577894. DOI: 10.1128/JVI.01522-15. View

19.

Kessl J, Kutluay S, Townsend D, Rebensburg S, Slaughter A, Larue R . HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis. Cell. 2016; 166(5):1257-1268.e12. PMC: 5003418. DOI: 10.1016/j.cell.2016.07.044. View

20.

Bernstein F, Koetzle T, Williams G, Meyer Jr E, Brice M, Rodgers J . The Protein Data Bank. A computer-based archival file for macromolecular structures. Eur J Biochem. 1977; 80(2):319-24. DOI: 10.1111/j.1432-1033.1977.tb11885.x. View