[Frontiers in Bioscience, Landmark, 25, 1538-1567, March 1, 2020]

Structural and strategic landscape of PIKK protein family and their inhibitors: an overview

Deekshi Angira1, Althaf Shaik1, Vijay Thiruvenkatam2

1Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India-382355, 2Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India-382355


1. Abstract
2. Introduction
3. Diverse kinases in PIKK protein family
    3.1. Mammalian target of Rapamycin (mTOR)
      3.1.1. Architectural framework of mTOR as the basis for inhibitor design
      3.1.2. mTOR inhibitors Rapamycin and rapalogs- allosteric inhibitors ATP competitive and irreversible inhibitor for mTOR
    3.2. Ataxia-telangiectasia mutated (ATM)
      3.2.1. Domain organization and active-site facet of ATM
      3.2.2. Quinolines as ATM inhibitors
    3.3. Ataxia-telangiectasia mutated- and Rad3-related (ATR)
      3.3.1. ATR-A key sensor to DNA damage repair and stalled replication forks
      3.3.2. Pyrazine amine derivatives as selective ATR inhibitors
    3.4. DNA dependent protein kinase catalytic subunit (DNA-PKcs)
      3.4.1. Structural dynamics of DNA-PKcs
      3.4.2. Inhibitors against DNA-PKcs
    3.5. Transformation/transcription domain-associated protein (TRRAP)
      3.5.1. TRRAP: An exceptional PIKK family member deficient in kinase activity
    3.6. Human Suppressor with morphological effect on genitalia family member (hSMG1)
      3.6.1. hSMG1: The mRNA surveillance protein
      3.6.2. Pyramidine amine deriviatives as selective hSMG inhibitors
4. Conclusion
5. Future perspectives
6. Acknowledgments
7. References


Phosphatidylinositol-3 kinase-related kinases (PIKKs) is a class of six unique serine/threonine kinases that are characterized as high molecular mass colossal proteins present in multicellular organisms. They predominantly regulate the innumerable eukaryotic cellular processes, for instance, cell-signaling cascades related to DNA damage and repair, cell growth and proliferation, cell cycle arrest, genome surveillance, gene expression and many other important yet diverse functions. A characteristic PIKK member comprises of an N-terminal HEAT domain, followed by FAT domain, a highly conserved kinase catalytic domain, and a C-terminal FATC domain. In this comprehensive review, we reassess and discuss various established functions of all the six PIKK members with each function corroborated by their structural topology. In addition to the domain architecture of these atypical kinases, their specific inhibitors have been briefly deliberated. This review gives us the impression of the emergent importance of PIKKs, which, despite of their complexity, are the hub of research with respect to the inhibitor development.


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Abbreviations: PIKKs: Phosphatidylinositol-3 kinase-related kinases , DNA: deoxyribonucleic acid, DDR: DNA damage response, hSMG1: Suppressor with morphological effect on genitalia family member, ATM: Ataxia telangiectasia mutated kinase, ATR: ATM- and Rad3-related kinase, DNA-PKcs: DNA dependent protein catalytic subunit, mTOR: mammalian target of rapamycin, TRRAP: Transformation-transactivation domain-associated protein, HEAT: Huntingtin, elongation factor 3 (EF3), protein phosphatase 2A (PP2A), and the yeast kinase TOR1, FAT: Frap, ATM, and TRRAP, FATC: FAT C-terminal, PRD: PIKK- regulatory domain, ATRIP: ATR interacting protein, MRN: Mre11-Rad50-Nbs1, UPF: up-frameshift, mRNA: messenger ribonucleic acid, FRAB: FKBP-rapamycin associated protein, RAFT: Rapamycin and FKBP target, mLST8: Mammalian lethal with SEC13 protein 8, NRD: Negative Regulatory Domain, FKBP12: FK506-binding protein12, FRB: FKBP12-Rapamycin-Binding (FRB) domain, HCT: Human colorectal carcinoma cell line, DSB: DNA double-strand breaks, BRCA1: Breast Cancer gene 1, Tel1: Telomere maintenance 1, EMT: Epithelial-to-Mesenchymal transition, JAK/STAT: Janus kinases/ Signal transducer and activator of transcription proteins, PD-L1: Programmed death-ligand 1, LBE: LST8-binding element, LID: LBE interacting domain, ADME: absorption, distribution, metabolism, excretion, MCM: Mini chromosomal maintenance, NHEJ: Non-homologous end joining, HR: Homologous recombination, XRCC4: X-ray repair cross-complementing protein 4, XLF: XRCC4-like factor, PNKP: Polynucleotide Kinase 3'-Phosphatase, SAF-A: Scaffold attachment factor A, hnRNP-U: Heterogeneous nuclear ribonucleoprotein U, PP6: Protein phosphatase 6, PP6R1: Protein phosphatase 6, regulatory subunit 1, siRNA: Small interfering RNA, HIV: Human Immunodeficiency Virus, GOLPH3: Golgi Phosphoprotein 3, PI3K: phosphatidylinositol 3-kinase, TIP60: Tat interactive protein, NPAT: Nuclear protein of the ATM locus, hGCN5: Histone acetyltransferase GCN5, MbII: Myc homology box II, TBP: TATA-binding protein, TFTC: TBP-free TAFII-containing complex, PCAF: P300/CBP-associated factor, HAT: Histone acetyltransferases, mdm2: Mouse double minute 2 homolog, Tra1: Transcription-associated protein 1, TPR: Tetratricopeptide, NMD: Nonsense-mediated mRNA decay, EJC: Exon junction complex, TNFα: Tumor Necrosis Factor-alpha, FLIPL: FLICE-like inhibitory protein, long form, CDK1: Cyclin dependent kinase 1

Key Words: PIKK, Phosphatidylinositol-3 kinase-related kinases, mTOR, mammalian target of rapamycin, ATR, ATM- and Rad3-related kinase, ATM, Ataxia telangiectasia mutated kinase, DNA-PKcs, DNA dependent protein catalytic subunit, TRRAP, Transformation-transactivation domain-associated protein, hSMG1, Suppressor with morphological effect on genitalia family member, DNA damage response

Send correspondence to: Vijay Thiruvenkatam, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India-382355, Tel: 91-9925907251, E-mail: vijay@iitgn.ac.in