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

Molecular Pharmacology
Xu LiuEric A Ortlund

Abstract

Both synthetic and endogenous glucocorticoids are important pharmaceutic drugs known to bind to the ligand-binding domain (LBD) of glucocorticoid receptor (GR), a member of the nuclear receptor (NR) superfamily. Ligand binding induces conformational changes within GR, resulting in subsequent DNA binding and differential coregulator recruitment, ultimately activating or repressing target gene expression. One of the most crucial coregulators is peroxisome proliferator-activated γ coactivator 1-α (PGC1α), which acts to regulate energy metabolism by directly interacting with GR to modulate gene expression. However, the mechanisms through which PGC1α senses GR conformation to drive transcription are not completely known. Here, an ancestral variant of the GR (AncGR2) LBD was used as a tool to produce stable protein for biochemical and structural studies. PGC1α is found to interact more tightly and form a more stable complex with AncGR2 LBD than nuclear receptor coactivator 2. We report the first high-resolution X-ray crystal structures of AncGR2 LBD in complex with PGC1α and dexamethasone (DEX) or hydrocortisone (HCY). Structural analyses reveal how distinct steroid drugs bind to GR with different affinities by unique hydrogen bonds ...Continue Reading

References

Feb 1, 1995·Protein Engineering·A C WallaceJ M Thornton
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Sep 12, 2001·Trends in Endocrinology and Metabolism : TEM·D Knutti, A Kralli
Dec 26, 2001·The Journal of Biological Chemistry·Yifei WuThomas P Burris
Nov 21, 2002·Pharmacology & Therapeutics·Heike SchäckeKhusru Asadullah
Oct 3, 2003·The Journal of Biological Chemistry·Dong-Ju ShinTimothy F Osborne
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Aug 2, 2005·Cell Metabolism·Jiandie LinBruce M Spiegelman
Aug 19, 2006·Journal of Computational Chemistry·Nicholas M Glykos
Dec 14, 2007·Nature·Katherine Henzler-Wildman, Dorothee Kern
Dec 28, 2007·Molecular and Cellular Biology·Kelly Suino-PowellH Eric Xu
Apr 11, 2009·Science·Nobuhiko Tokuriki, Dan S Tawfik
Jun 3, 2009·Nature Reviews. Endocrinology·George P Chrousos
Nov 17, 2009·Journal of Molecular Biology·Guillaume A SchochArmin Ruf
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Jan 17, 2012·Structure·Travis S HughesDouglas J Kojetin
Mar 23, 2012·The Journal of Biological Chemistry·Jeffrey A KohnEric A Ortlund
Jul 24, 2012·Trends in Endocrinology and Metabolism : TEM·Richard C ScarpullaDaniel P Kelly
Aug 21, 2013·Trends in Pharmacological Sciences·Mahita Kadmiel, John A Cidlowski
Apr 18, 2014·Nature·Hesam N MotlaghVincent J Hilser
Apr 26, 2014·Cell Research·Yuanzheng HeH Eric Xu
Sep 10, 2014·Acta Crystallographica. Section D, Biological Crystallography·Robert A NichollsGarib N Murshudov
Aug 9, 2016·Methods in Enzymology·S Bowerman, J Wereszczynski
Jan 6, 2017·Nature Reviews. Molecular Cell Biology·Emily R WeikumKeith R Yamamoto
Apr 2, 2017·Molecular Pharmacology·Suzanne G MaysEric A Ortlund
Jul 12, 2017·Journal of Thrombosis and Haemostasis : JTH·W DengR Li

❮ Previous
Next ❯

Citations

Sep 13, 2020·Proceedings of the National Academy of Sciences of the United States of America·Xu LiuEric A Ortlund
Dec 19, 2020·Scientific Reports·Suzanne G MaysEric A Ortlund
Jun 23, 2021·Journal of Chemical Information and Modeling·Giuseppina La SalaAndrey I Frolov
Apr 20, 2021·Journal of the National Cancer Institute·Kelly McCastlainKirsten K Ness
Jul 22, 2021·Proceedings of the National Academy of Sciences of the United States of America·Filipp FrankEric A Ortlund
Oct 29, 2021·Biochemical Society Transactions·Filipp FrankXu Liu

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.