Conserved functional motifs of the nuclear receptor superfamily as potential pharmacological targets

Papageorgiou,Louis; Shalzi,Livia; Efthimiadou,Aspasia; Bacopoulou,Flora; Chrousos,George P.; Eliopoulos,Elias; Vlachakis,Dimitrios

doi:10.3892/ije.2021.3

Conserved functional motifs of the nuclear receptor superfamily as potential pharmacological targets

Authors:
- Louis Papageorgiou
- Livia Shalzi
- Aspasia Efthimiadou
- Flora Bacopoulou
- George P. Chrousos
- Elias Eliopoulos
- Dimitrios Vlachakis
View Affiliations

Affiliations: Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece, Department of Soil Science of Athens, Institute of Soil and Water Resources, Hellenic Agricultural Organization‑Demeter, 14123 Lycovrisi, Greece, University Research Institute of Maternal and Child Health and Precision Medicine, and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, ‘Aghia Sophia’ Children's Hospital, 11527 Athens, Greece
Published online on: June 2, 2021 https://doi.org/10.3892/ije.2021.3
Article Number: 3
Copyright: © Papageorgiou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nuclear receptors (NRs) are one of the most diverse and well-reported family of proteins. They are involved in numerous cellular processes as they play pivotal roles in cell signaling and the cell cycle. The participation of NRs in various applications in medicine and biology has greatly attracted the interest of the pharmaceutical industry for the discovery of novel and/or improved drugs for the treatment of several diseases, including cancer, diabetes or infertility. In the present study, in an effort to elucidate the molecular function of this superfamily and to identify novel pharmacological targets, a comprehensive sequence and structural analysis was performed using all available information from a repertoire of depositories. Functional conserved motifs were identified and analyzed with regards to their potential roles and implications in a number of biological processes. The essential differences among them were also addressed and discussed. In addition, these motifs were characterized in the main groups of the NRs, such as that of the steroid hormone receptors.

View Figures

View References

1	Novac N and Heinzel T: Nuclear receptors: Overview and classification. Curr Drug Targets Inflamm Allergy. 3:335–346. 2004.PubMed/NCBI View Article : Google Scholar
2	Shi Y: Orphan nuclear receptors in drug discovery. Drug Discov Today. 12:440–445. 2007.PubMed/NCBI View Article : Google Scholar
3	Ottow E and Weinmann H (eds): Nuclear Receptors as Drug Targets. In: Methods and Principles in Medicinal Chemistry. John Wiley & Sons, Inc., Hoboken NJ, 2008.
4	Huang P, Chandra V and Rastinejad F: Structural overview of the nuclear receptor superfamily: Insights into physiology and therapeutics. Annu Rev Physiol. 72:247–272. 2010.PubMed/NCBI View Article : Google Scholar
5	Pearce KH, Iannone MA, Simmons CA and Gray JG: Discovery of novel nuclear receptor modulating ligands: An integral role for peptide interaction profiling. Drug Discov Today. 9:741–751. 2004.PubMed/NCBI View Article : Google Scholar
6	Laudet V: Evolution of the nuclear receptor superfamily: Early diversification from an ancestral orphan receptor. J Mol Endocrinol. 19:207–226. 1997.PubMed/NCBI View Article : Google Scholar
7	Weikum ER, Liu X and Ortlund EA: The nuclear receptor superfamily: A structural perspective. Protein Sci. 27:1876–1892. 2018.PubMed/NCBI View Article : Google Scholar
8	Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, Bork P, Das U, Daugherty L, Duquenne L, et al: InterPro: The integrative protein signature database. Nucleic Acids Res. 37 (Database):D211–D215. 2009.PubMed/NCBI View Article : Google Scholar
9	Vlachakis D, Papageorgiou L, Papadaki A, Georga M, Kossida S and Eliopoulos E: An updated evolutionary study of the Notch family reveals a new ancient origin and novel invariable motifs as potential pharmacological targets. PeerJ. 8(e10334)2020.PubMed/NCBI View Article : Google Scholar
10	Papageorgiou L, Loukatou S, Sofia K, Maroulis D and Vlachakis D: An updated evolutionary study of Flaviviridae NS3 helicase and NS5 RNA-dependent RNA polymerase reveals novel invariable motifs as potential pharmacological targets. Mol Biosyst. 12:2080–2093. 2016.PubMed/NCBI View Article : Google Scholar
11	Papageorgiou L, Megalooikonomou V and Vlachakis D: Genetic and structural study of DNA-directed RNA polymerase II of Trypanosoma brucei, towards the designing of novel antiparasitic agents. PeerJ. 5(e3061)2017.PubMed/NCBI View Article : Google Scholar
12	Waterhouse AM, Procter JB, Martin DM, Clamp M and Barton GJ: Jalview Version 2 - a multiple sequence alignment editor and analysis workbench. Bioinformatics. 25:1189–1191. 2009.PubMed/NCBI View Article : Google Scholar
13	Sobie EA: An introduction to MATLAB. Sci Signal. 4(tr7)2011.PubMed/NCBI View Article : Google Scholar
14	Thuillard M: Minimizing contradictions on circular order of phylogenic trees. Evol Bioinform Online. 3:267–277. 2007.PubMed/NCBI
15	Crow JF: Thomas H. Jukes (1906-1999). Genetics. 154:955–956. 2000.PubMed/NCBI
16	Gibbons FD and Roth FP: Judging the quality of gene expression-based clustering methods using gene annotation. Genome Res. 12:1574–1581. 2002.PubMed/NCBI View Article : Google Scholar
17	Leach A: Molecular modelling: Principles and applications. 2nd edition. Pearson, London, 2021.
18	Kumar S, Stecher G and Tamura K: MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. Mol Biol Evol. 33:1870–1874. 2016.PubMed/NCBI View Article : Google Scholar
19	He Y, Yi W, Suino-Powell K, Zhou XE, Tolbert WD, Tang X, Yang J, Yang H, Shi J, Hou L, et al: Structures and mechanism for the design of highly potent glucocorticoids. Cell Res. 24:713–726. 2014.PubMed/NCBI View Article : Google Scholar
20	Hemmerling M, Nilsson S, Edman K, Eirefelt S, Russell W, Hendrickx R, Johnsson E, Kärrman Mårdh C, Berger M, Rehwinkel H, et al: Selective nonsteroidal glucocorticoid receptor modulators for the inhaled treatment of pulmonary diseases. J Med Chem. 60:8591–8605. 2017.PubMed/NCBI View Article : Google Scholar
21	Liu X, Wang Y and Ortlund EA: First high-resolution crystal structures of the glucocorticoid receptor ligand-binding domain-peroxisome proliferator-activated γ coactivator 1-α complex with endogenous and synthetic glucocorticoids. Mol Pharmacol. 96:408–417. 2019.PubMed/NCBI View Article : Google Scholar
22	Weikum ER, Liu X and Ortlund EA: The nuclear receptor superfamily: A structural perspective. Protein Sci. 27:1876–1892. 2018.PubMed/NCBI View Article : Google Scholar
23	Pawlak M, Lefebvre P and Staels B: General molecular biology and architecture of nuclear receptors. Curr Top Med Chem. 12:486–504. 2012.PubMed/NCBI View Article : Google Scholar
24	Mitsis T, Papageorgiou L, Efthimiadou A, Bacopoulou F, Vlachakis D, Chrousos GP and Eliopoulos E: A comprehensive structural and functional analysis of the ligand binding domain of the nuclear receptor superfamily reveals highly conserved signaling motifs and two distinct canonical forms through evolution. World Acad Sci J. 1:264–274. 2019.
25	Porter BA, Ortiz MA, Bratslavsky G and Kotula L: Structure and function of the nuclear receptor superfamily and current targeted therapies of prostate cancer. Cancers (Basel). 11(E1852)2019.PubMed/NCBI View Article : Google Scholar
26	Pace NJ and Weerapana E: Zinc-binding cysteines: Diverse functions and structural motifs. Biomolecules. 4:419–434. 2014.PubMed/NCBI View Article : Google Scholar
27	Plevin MJ, Mills MM and Ikura M: The LxxLL motif: A multifunctional binding sequence in transcriptional regulation. Trends Biochem Sci. 30:66–69. 2005.PubMed/NCBI View Article : Google Scholar
28	Loinder K and Söderström M: Functional analyses of an LXXLL motif in nuclear receptor corepressor (N-CoR). J Steroid Biochem Mol Biol. 91:191–196. 2004.PubMed/NCBI View Article : Google Scholar
29	Evans RM: The steroid and thyroid hormone receptor superfamily. Science. 240:889–895. 1988.PubMed/NCBI View Article : Google Scholar
30	Barish GD, Downes M, Alaynick WA, Yu RT, Ocampo CB, Bookout AL, Mangelsdorf DJ and Evans RM: A Nuclear Receptor Atlas: Macrophage activation. Mol Endocrinol. 19:2466–2477. 2005.PubMed/NCBI View Article : Google Scholar
31	Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM and Mangelsdorf DJ: Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 126:789–799. 2006.PubMed/NCBI View Article : Google Scholar
32	Sonoda J, Pei L and Evans RM: Nuclear receptors: Decoding metabolic disease. FEBS Lett. 582:2–9. 2008.PubMed/NCBI View Article : Google Scholar
33	Raftopoulou S, Nicolaides NC, Papageorgiou L, Amfilochiou A, Zakinthinos SG, George P, Eliopoulos E, Chrousos GP and Vlachakis D: Structural Study of the DNA: Clock/Bmal1 Complex Provides Insights for the Role of Cortisol, hGR, and HPA Axis in Stress Management and Sleep Disorders. Adv Exp Med Biol. 1195:59–71. 2020.PubMed/NCBI View Article : Google Scholar
34	Weinberger C, Hollenberg SM, Ong ES, Harmon JM, Brower ST, Cidlowski J, Thompson EB, Rosenfeld MG and Evans RM: Identification of human glucocorticoid receptor complementary DNA clones by epitope selection. Science. 228:740–742. 1985.PubMed/NCBI View Article : Google Scholar
35	Greene GL, Gilna P, Waterfield M, Baker A, Hort Y and Shine J: Sequence and expression of human estrogen receptor complementary DNA. Science. 231:1150–1154. 1986.PubMed/NCBI View Article : Google Scholar
36	Krust A, Green S, Argos P, Kumar V, Walter P, Bornert JM and Chambon P: The chicken oestrogen receptor sequence: Homology with v-erbA and the human oestrogen and glucocorticoid receptors. EMBO J. 5:891–897. 1986.PubMed/NCBI
37	Weinberger C, Giguère V, Hollenberg SM, Thompson C, Arriza J and Evans RM: Human steroid receptors and erb-A gene products form a superfamily of enhancer-binding proteins. Clin Physiol Biochem. 5:179–189. 1987.PubMed/NCBI
38	Owen GI and Zelent A: Origins and evolutionary diversification of the nuclear receptor superfamily. Cell Mol Life Sci. 57:809–827. 2000.PubMed/NCBI View Article : Google Scholar
39	Shiau AK, Coward P, Schwarz M and Lehmann JM: Orphan nuclear receptors: From new ligand discovery technologies to novel signaling pathways. Curr Opin Drug Discov Devel. 4:575–590. 2001.PubMed/NCBI
40	Kliewer SA, Lehmann JM and Willson TM: Orphan nuclear receptors: Shifting endocrinology into reverse. Science. 284:757–760. 1999.PubMed/NCBI View Article : Google Scholar
41	Aranda A and Pascual A: Nuclear hormone receptors and gene expression. Physiol Rev. 81:1269–1304. 2001.PubMed/NCBI View Article : Google Scholar
42	Chen T: Nuclear receptor drug discovery. Curr Opin Chem Biol. 12:418–426. 2008.PubMed/NCBI View Article : Google Scholar
43	Giannini A, Russo E, Mannella P and Simoncini T: Selective steroid receptor modulators in reproductive medicine. Minerva Ginecol. 67:431–455. 2015.PubMed/NCBI
44	Rhen T and Cidlowski JA: Antiinflammatory action of glucocorticoids - new mechanisms for old drugs. N Engl J Med. 353:1711–1723. 2005.PubMed/NCBI View Article : Google Scholar
45	Thornton JW: Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci USA. 98:5671–5676. 2001.PubMed/NCBI View Article : Google Scholar
46	Bridgham JT, Carroll SM and Thornton JW: Evolution of hormone-receptor complexity by molecular exploitation. Science. 312:97–101. 2006.PubMed/NCBI View Article : Google Scholar
47	Magadum S, Banerjee U, Murugan P, Gangapur D and Ravikesavan R: Gene duplication as a major force in evolution. J Genet. 92:155–161. 2013.PubMed/NCBI View Article : Google Scholar
48	Baker ME: Steroid receptor phylogeny and vertebrate origins. Mol Cell Endocrinol. 135:101–107. 1997.PubMed/NCBI View Article : Google Scholar
49	Laudet V, Hänni C, Coll J, Catzeflis F and Stéhelin D: Evolution of the nuclear receptor gene superfamily. EMBO J. 11:1003–1013. 1992.PubMed/NCBI
50	Escriva H, Safi R, Hänni C, Langlois MC, Saumitou-Laprade P, Stehelin D, Capron A, Pierce R and Laudet V: Ligand binding was acquired during evolution of nuclear receptors. Proc Natl Acad Sci USA. 94:6803–6808. 1997.PubMed/NCBI View Article : Google Scholar