5g3j: Difference between revisions

Latest revision as of 13:37, 26 July 2023

Discovery of New Selective Glucocorticoid Receptor Agonist Leads

Structural highlights

5g3j is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	CPS, E7T, EDO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GCR_HUMAN Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.^[1] ^[2] ^[3] ^[4] ^[5]

Function

GCR_HUMAN Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.^[6]

Publication Abstract from PubMed

We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.

Discovery of new selective glucocorticoid receptor agonist leads.,Berger M, Rehwinkel H, Schmees N, Schacke H, Edman K, Wissler L, Reichel A, Jaroch S Bioorg Med Chem Lett. 2017 Feb 1;27(3):437-442. doi: 10.1016/j.bmcl.2016.12.047. , Epub 2016 Dec 23. PMID:28043796^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun;87(6):2658-67. PMID:12050230
↑ Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb;87(2):680-6. PMID:1704018 doi:https://dx.doi.org/10.1172/JCI115046
↑ Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May;91(5):1918-25. PMID:7683692 doi:https://dx.doi.org/10.1172/JCI116410
↑ Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep;55(3):363-71. PMID:11589680
↑ Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov;86(11):5600-8. PMID:11701741
↑ Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Oct;1813(10):1814-21. doi:, 10.1016/j.bbamcr.2011.05.014. Epub 2011 Jun 2. PMID:21664385 doi:10.1016/j.bbamcr.2011.05.014
↑ Berger M, Rehwinkel H, Schmees N, Schacke H, Edman K, Wissler L, Reichel A, Jaroch S. Discovery of new selective glucocorticoid receptor agonist leads. Bioorg Med Chem Lett. 2017 Feb 1;27(3):437-442. doi: 10.1016/j.bmcl.2016.12.047. , Epub 2016 Dec 23. PMID:28043796 doi:https://dx.doi.org/10.1016/j.bmcl.2016.12.047

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OCA

[1] Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun;87(6):2658-67. PMID:12050230

[2] Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb;87(2):680-6. PMID:1704018 doi:https://dx.doi.org/10.1172/JCI115046

[3] Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May;91(5):1918-25. PMID:7683692 doi:https://dx.doi.org/10.1172/JCI116410

[4] Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep;55(3):363-71. PMID:11589680

[5] Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov;86(11):5600-8. PMID:11701741

[6] Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Oct;1813(10):1814-21. doi:, 10.1016/j.bbamcr.2011.05.014. Epub 2011 Jun 2. PMID:21664385 doi:10.1016/j.bbamcr.2011.05.014

[7] Berger M, Rehwinkel H, Schmees N, Schacke H, Edman K, Wissler L, Reichel A, Jaroch S. Discovery of new selective glucocorticoid receptor agonist leads. Bioorg Med Chem Lett. 2017 Feb 1;27(3):437-442. doi: 10.1016/j.bmcl.2016.12.047. , Epub 2016 Dec 23. PMID:28043796 doi:https://dx.doi.org/10.1016/j.bmcl.2016.12.047

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[2]

[3]

[4]

[5]

[6]

[7]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5g3j is ON HOLD  until Paper Publication
+==Discovery of New Selective Glucocorticoid Receptor Agonist Leads==
+<StructureSection load='5g3j' size='340' side='right'caption='[[5g3j]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5g3j]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G3J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G3J FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CPS:3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE'>CPS</scene>, <scene name='pdbligand=E7T:5-[[(1S,2R,4R)-4-ETHYL-6,7-BIS(FLUORANYL)-2,5-BIS(OXIDANYL)-2-(TRIFLUOROMETHYL)-3,4-DIHYDRO-1H-NAPHTHALEN-1-YL]AMINO]-1H-QUINOLIN-2-ONE'>E7T</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5g3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g3j OCA], [https://pdbe.org/5g3j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g3j RCSB], [https://www.ebi.ac.uk/pdbsum/5g3j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g3j ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[https://omim.org/entry/138040 138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.
-Authors: Berger, M., Edman, K., Wissler, L., Neuhaus, R., Rehwinkel, H., Schacke, H., Jaroch, S.
+Discovery of new selective glucocorticoid receptor agonist leads.,Berger M, Rehwinkel H, Schmees N, Schacke H, Edman K, Wissler L, Reichel A, Jaroch S Bioorg Med Chem Lett. 2017 Feb 1;27(3):437-442. doi: 10.1016/j.bmcl.2016.12.047. , Epub 2016 Dec 23. PMID:28043796<ref>PMID:28043796</ref>
-Description: Discovery of Novel Selective Glucocorticoid Receptor Agonist Leads
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Edman, K]]
+<div class="pdbe-citations 5g3j" style="background-color:#fffaf0;"></div>
-[[Category: Jaroch, S]]
-[[Category: Schacke, H]]
+==See Also==
-[[Category: Wissler, L]]
+*[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]]
-[[Category: Berger, M]]
+== References ==
-[[Category: Neuhaus, R]]
+<references/>
-[[Category: Rehwinkel, H]]
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Berger M]]
+[[Category: Edman K]]
+[[Category: Jaroch S]]
+[[Category: Neuhaus R]]
+[[Category: Rehwinkel H]]
+[[Category: Schacke H]]
+[[Category: Wissler L]]

5g3j: Difference between revisions

Latest revision as of 13:37, 26 July 2023

Discovery of New Selective Glucocorticoid Receptor Agonist Leads

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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