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5j0d

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Revision as of 07:23, 10 June 2020

Crystal structure of the bromodomain of human CREBBP in complex with a benzoxazepine compound

Structural highlights

5j0d is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	CREBBP, CBP (HUMAN)
Activity:	Histone acetyltransferase, with EC number 2.3.1.48
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CBP_HUMAN] Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:180849]. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies.^[1] ^[2] ^[3] ^[4]

Function

[CBP_HUMAN] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein-protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112. We present comprehensive SAR of this inhibitor class as well as demonstration of cellular on target activity of the most potent and selective inhibitor TPOP146, which showed 134 nM affinity for CBP with excellent selectivity over other bromodomains.

Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors.,Popp TA, Tallant C, Rogers C, Fedorov O, Brennan PE, Muller S, Knapp S, Bracher F J Med Chem. 2016 Sep 27. PMID:27673482^[9]

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

References

↑ Murata T, Kurokawa R, Krones A, Tatsumi K, Ishii M, Taki T, Masuno M, Ohashi H, Yanagisawa M, Rosenfeld MG, Glass CK, Hayashi Y. Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome. Hum Mol Genet. 2001 May 1;10(10):1071-6. PMID:11331617
↑ Bartsch O, Locher K, Meinecke P, Kress W, Seemanova E, Wagner A, Ostermann K, Rodel G. Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet. 2002 Jul;39(7):496-501. PMID:12114483
↑ Kalkhoven E, Roelfsema JH, Teunissen H, den Boer A, Ariyurek Y, Zantema A, Breuning MH, Hennekam RC, Peters DJ. Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome. Hum Mol Genet. 2003 Feb 15;12(4):441-50. PMID:12566391
↑ Roelfsema JH, White SJ, Ariyurek Y, Bartholdi D, Niedrist D, Papadia F, Bacino CA, den Dunnen JT, van Ommen GJ, Breuning MH, Hennekam RC, Peters DJ. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet. 2005 Apr;76(4):572-80. Epub 2005 Feb 10. PMID:15706485 doi:S0002-9297(07)62869-9
↑ Zhang W, Bieker JJ. Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9855-60. PMID:9707565
↑ Hung HL, Kim AY, Hong W, Rakowski C, Blobel GA. Stimulation of NF-E2 DNA binding by CREB-binding protein (CBP)-mediated acetylation. J Biol Chem. 2001 Apr 6;276(14):10715-21. Epub 2001 Jan 11. PMID:11154691 doi:10.1074/jbc.M007846200
↑ Masumi A, Yamakawa Y, Fukazawa H, Ozato K, Komuro K. Interferon regulatory factor-2 regulates cell growth through its acetylation. J Biol Chem. 2003 Jul 11;278(28):25401-7. Epub 2003 May 7. PMID:12738767 doi:10.1074/jbc.M213037200
↑ Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T. P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain. J Bone Miner Res. 2003 Aug;18(8):1419-29. PMID:12929931 doi:http://dx.doi.org/10.1359/jbmr.2003.18.8.1419
↑ Popp TA, Tallant C, Rogers C, Fedorov O, Brennan PE, Muller S, Knapp S, Bracher F. Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors. J Med Chem. 2016 Sep 27. PMID:27673482 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00774

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5j0d"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the bromodomain of human CREBBP in complex with a benzoxazepine compound==
-<StructureSection load='5j0d' size='340' side='right' caption='[[5j0d]], [[Resolution|resolution]] 1.05&Aring;' scene=''>
+<StructureSection load='5j0d' size='340' side='right'caption='[[5j0d]], [[Resolution|resolution]] 1.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j0d]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J0D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J0D FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j0d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J0D OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J0D FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6F9:7-(3,5-DIMETHOXYPHENYL)-N-[(3S)-1-METHYLPIPERIDIN-3-YL]-4-PROPANOYL-2,3,4,5-TETRAHYDRO-1,4-BENZOXAZEPINE-9-CARBOXAMIDE'>6F9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6F9:7-(3,5-DIMETHOXYPHENYL)-N-[(3S)-1-METHYLPIPERIDIN-3-YL]-4-PROPANOYL-2,3,4,5-TETRAHYDRO-1,4-BENZOXAZEPINE-9-CARBOXAMIDE'>6F9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CREBBP, CBP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j0d OCA], [http://pdbe.org/5j0d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j0d RCSB], [http://www.ebi.ac.uk/pdbsum/5j0d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j0d ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5j0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j0d OCA], [http://pdbe.org/5j0d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j0d RCSB], [http://www.ebi.ac.uk/pdbsum/5j0d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j0d ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 </div>
 <div class="pdbe-citations 5j0d" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[CREB-binding protein 3D structures|CREB-binding protein 3D structures]]
 == References ==
 <references/>
@@ Line 26: / Line 30: @@
 </StructureSection>
 [[Category: Histone acetyltransferase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Arrowsmith, C H]]
 [[Category: Bountra, C]]

5j0d

From Proteopedia

Revision as of 07:23, 10 June 2020

Crystal structure of the bromodomain of human CREBBP in complex with a benzoxazepine compound

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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