5ktu

From Proteopedia

(Difference between revisions)

Revision as of 06:34, 5 August 2020

Crystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold

Structural highlights

5ktu is a 2 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

The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 muM, BRET IC50 = 0.41 muM, BRD4(1) IC50 = 13 muM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.,Crawford TD, Romero FA, Lai KW, Tsui V, Taylor AM, de Leon Boenig G, Noland CL, Murray J, Ly J, Choo EF, Hunsaker TL, Chan EW, Merchant M, Kharbanda S, Gascoigne KE, Kaufman S, Beresini MH, Liao J, Liu W, Chen KX, Chen Z, Conery AR, Cote A, Jayaram H, Jiang Y, Kiefer JR, Kleinheinz T, Li Y, Maher J, Pardo E, Poy F, Spillane KL, Wang F, Wang J, Wei X, Xu Z, Xu Z, Yen I, Zawadzke L, Zhu X, Bellon S, Cummings R, Cochran AG, Albrecht BK, Magnuson S J Med Chem. 2016 Sep 28. PMID:27682507^[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
↑ Crawford TD, Romero FA, Lai KW, Tsui V, Taylor AM, de Leon Boenig G, Noland CL, Murray J, Ly J, Choo EF, Hunsaker TL, Chan EW, Merchant M, Kharbanda S, Gascoigne KE, Kaufman S, Beresini MH, Liao J, Liu W, Chen KX, Chen Z, Conery AR, Cote A, Jayaram H, Jiang Y, Kiefer JR, Kleinheinz T, Li Y, Maher J, Pardo E, Poy F, Spillane KL, Wang F, Wang J, Wei X, Xu Z, Xu Z, Yen I, Zawadzke L, Zhu X, Bellon S, Cummings R, Cochran AG, Albrecht BK, Magnuson S. Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300. J Med Chem. 2016 Sep 28. PMID:27682507 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01022

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/5ktu"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold==
-<StructureSection load='5ktu' size='340' side='right' caption='[[5ktu]], [[Resolution|resolution]] 1.38&Aring;' scene=''>
+<StructureSection load='5ktu' size='340' side='right'caption='[[5ktu]], [[Resolution|resolution]] 1.38&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ktu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KTU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KTU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ktu]] is a 2 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=5KTU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5KTU FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XB:1-(3-PHENYLAZANYL-1,4,6,7-TETRAHYDROPYRAZOLO[4,3-C]PYRIDIN-5-YL)ETHANONE'>6XB</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6XB:1-(3-PHENYLAZANYL-1,4,6,7-TETRAHYDROPYRAZOLO[4,3-C]PYRIDIN-5-YL)ETHANONE'>6XB</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=5ktu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ktu OCA], [http://pdbe.org/5ktu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ktu RCSB], [http://www.ebi.ac.uk/pdbsum/5ktu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ktu 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=5ktu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ktu OCA], [http://pdbe.org/5ktu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ktu RCSB], [http://www.ebi.ac.uk/pdbsum/5ktu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ktu ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 </div>
 <div class="pdbe-citations 5ktu" 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: Bellon, S F]]
 [[Category: Jayaram, H]]

5ktu

From Proteopedia

Revision as of 06:34, 5 August 2020

Crystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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