5y7w

Crystal structure of the Nco-A1 PAS-B domain with YL-2Crystal structure of the Nco-A1 PAS-B domain with YL-2

Structural highlights

5y7w is a 4 chain structure with sequence from Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.25Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NCOA1_MOUSE 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]

Publication Abstract from PubMed

The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.

Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction.,Lee Y, Yoon H, Hwang SM, Shin MK, Lee JH, Oh M, Im SH, Song J, Lim HS J Am Chem Soc. 2017 Nov 1. doi: 10.1021/jacs.7b08972. PMID:29090910^[5]

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

References

↑ Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996 May 3;85(3):403-14. PMID:8616895
↑ Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai MJ, O'Malley BW. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 1998 Mar 20;279(5358):1922-5. PMID:9506940
↑ Picard F, Gehin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, Auwerx J. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002 Dec 27;111(7):931-41. PMID:12507421
↑ Xie H, Sadim MS, Sun Z. RORgammat recruits steroid receptor coactivators to ensure thymocyte survival. J Immunol. 2005 Sep 15;175(6):3800-9. PMID:16148126
↑ Lee Y, Yoon H, Hwang SM, Shin MK, Lee JH, Oh M, Im SH, Song J, Lim HS. Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction. J Am Chem Soc. 2017 Nov 1. doi: 10.1021/jacs.7b08972. PMID:29090910 doi:http://dx.doi.org/10.1021/jacs.7b08972

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OCA

[1] Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996 May 3;85(3):403-14. PMID:8616895

[2] Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai MJ, O'Malley BW. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 1998 Mar 20;279(5358):1922-5. PMID:9506940

[3] Picard F, Gehin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, Auwerx J. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002 Dec 27;111(7):931-41. PMID:12507421

[4] Xie H, Sadim MS, Sun Z. RORgammat recruits steroid receptor coactivators to ensure thymocyte survival. J Immunol. 2005 Sep 15;175(6):3800-9. PMID:16148126

[5] Lee Y, Yoon H, Hwang SM, Shin MK, Lee JH, Oh M, Im SH, Song J, Lim HS. Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction. J Am Chem Soc. 2017 Nov 1. doi: 10.1021/jacs.7b08972. PMID:29090910 doi:http://dx.doi.org/10.1021/jacs.7b08972

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