6w9h: Difference between revisions

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New page: '''Unreleased structure''' The entry 6w9h is ON HOLD Authors: Sack, J.S. Description: SUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTS...
 
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'''Unreleased structure'''


The entry 6w9h is ON HOLD
==SUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTS==
<StructureSection load='6w9h' size='340' side='right'caption='[[6w9h]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6w9h]] is a 1 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=6W9H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W9H 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]] 1.995&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TKJ:4-{(3R)-3-[4-(benzyloxy)phenyl]-3-[(4-fluorophenyl)sulfonyl]pyrrolidine-1-carbonyl}-1lambda~6~-thiane-1,1-dione'>TKJ</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=6w9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w9h OCA], [https://pdbe.org/6w9h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w9h RCSB], [https://www.ebi.ac.uk/pdbsum/6w9h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w9h ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.
== Function ==
[https://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Substituted benzyloxy aryl compound 2 was identified as an RORgammat agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.


Authors: Sack, J.S.
Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORgammat) agonists.,Harikrishnan LS, Gill P, Kamau MG, Qin LY, Ruan Z, O'Malley D, Huynh T, Stachura S, Cavallaro CL, Lu Z, J-W Duan J, Weigelt CA, Sack JS, Ruzanov M, Khan J, Gururajan M, Wong JJ, Huang Y, Yarde M, Li Z, Chen C, Sun H, Borowski V, Murtaza A, Fink BE Bioorg Med Chem Lett. 2020 Jun 15;30(12):127204. doi: 10.1016/j.bmcl.2020.127204., Epub 2020 Apr 20. PMID:32334911<ref>PMID:32334911</ref>


Description: SUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTS
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Sack, J.S]]
<div class="pdbe-citations 6w9h" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Sack JS]]

Latest revision as of 17:19, 18 October 2023

SUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTSSUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTS

Structural highlights

6w9h is a 1 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 1.995Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NCOA1_HUMAN Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.

Function

RORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.NCOA1_HUMAN Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Substituted benzyloxy aryl compound 2 was identified as an RORgammat agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORgammat) agonists.,Harikrishnan LS, Gill P, Kamau MG, Qin LY, Ruan Z, O'Malley D, Huynh T, Stachura S, Cavallaro CL, Lu Z, J-W Duan J, Weigelt CA, Sack JS, Ruzanov M, Khan J, Gururajan M, Wong JJ, Huang Y, Yarde M, Li Z, Chen C, Sun H, Borowski V, Murtaza A, Fink BE Bioorg Med Chem Lett. 2020 Jun 15;30(12):127204. doi: 10.1016/j.bmcl.2020.127204., Epub 2020 Apr 20. PMID:32334911[8]

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

References

  1. ↑ Kalkhoven E, Valentine JE, Heery DM, Parker MG. Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J. 1998 Jan 2;17(1):232-43. PMID:9427757 doi:10.1093/emboj/17.1.232
  2. ↑ Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354-7. PMID:7481822
  3. ↑ Hayashi Y, Ohmori S, Ito T, Seo H. A splicing variant of Steroid Receptor Coactivator-1 (SRC-1E): the major isoform of SRC-1 to mediate thyroid hormone action. Biochem Biophys Res Commun. 1997 Jul 9;236(1):83-7. PMID:9223431 doi:10.1006/bbrc.1997.6911
  4. ↑ Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997 Sep 11;389(6647):194-8. PMID:9296499 doi:10.1038/38304
  5. ↑ Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor induction of gene transcription: a two-step model. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7879-84. PMID:9223281
  6. ↑ Liu Z, Wong J, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9485-90. PMID:10449719
  7. ↑ Litterst CM, Kliem S, Marilley D, Pfitzner E. NCoA-1/SRC-1 is an essential coactivator of STAT5 that binds to the FDL motif in the alpha-helical region of the STAT5 transactivation domain. J Biol Chem. 2003 Nov 14;278(46):45340-51. Epub 2003 Sep 3. PMID:12954634 doi:http://dx.doi.org/10.1074/jbc.M303644200
  8. ↑ Harikrishnan LS, Gill P, Kamau MG, Qin LY, Ruan Z, O'Malley D, Huynh T, Stachura S, Cavallaro CL, Lu Z, J-W Duan J, Weigelt CA, Sack JS, Ruzanov M, Khan J, Gururajan M, Wong JJ, Huang Y, Yarde M, Li Z, Chen C, Sun H, Borowski V, Murtaza A, Fink BE. Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORgammat) agonists. Bioorg Med Chem Lett. 2020 Jun 15;30(12):127204. doi: 10.1016/j.bmcl.2020.127204., Epub 2020 Apr 20. PMID:32334911 doi:http://dx.doi.org/10.1016/j.bmcl.2020.127204

6w9h, resolution 2.00Å

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