4tqn

From Proteopedia

(Difference between revisions)

Revision as of 19:47, 9 March 2016

Crystal structure of the bromodomain of human CREBBP in complex with UL04

Structural highlights

4tqn is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Histone acetyltransferase, with EC number 2.3.1.48
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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

We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based virtual screening. First a library of about 100,000 molecular fragments was docked with evaluation of force field energy and desolvation penalty. Then the top ranking fragments were used for selecting molecules for flexible docking from a library of nearly two million compounds. Upon flexible docking and ranking, only 17 molecules from the two-million library were tested in vitro, and two of them showed an equilibrium dissociation constant smaller than 30 microM. The 4-acyl pyrrole hit 1 was optimized by taking into account the binding mode obtained by docking and molecular dynamics simulations which suggested how to improve the interactions with the side chain of Arg1173 at the rim of the binding site. The efficient hit optimization (only two synthesized derivatives) yielded the 4-acyl pyrrole derivative 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non-hydrogen atom. The acyl benzene hit 9 was also optimized by improving the polar interactions with the side chain of Arg1173, which resulted in a series of derivatives with nanomolar potencies, good ligand efficiency as well as high selectivity (see back to back paper). The in silico predicted binding mode of the acyl benzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain.

Discovery of CREBBP Bromodomain Inhibitors by High-throughput Docking and Hit Optimization Guided by Molecular Dynamics.,Xu M, Unzue A, Dong J, Spiliotopoulos D, Nevado C, Caflisch A J Med Chem. 2015 Jun 30. PMID:26125948^[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
↑ Xu M, Unzue A, Dong J, Spiliotopoulos D, Nevado C, Caflisch A. Discovery of CREBBP Bromodomain Inhibitors by High-throughput Docking and Hit Optimization Guided by Molecular Dynamics. J Med Chem. 2015 Jun 30. PMID:26125948 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00171

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4tqn"

Categories: Histone acetyltransferase | Caflisch, A | Dong, J | Transcription/inhibitor | Transferase

@@ Line 1: / Line 1: @@
 ==Crystal structure of the bromodomain of human CREBBP in complex with UL04==
 <StructureSection load='4tqn' size='340' side='right' caption='[[4tqn]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=UL4:3-[(5-ACETYL-2-ETHOXYPHENYL)CARBAMOYL]BENZOIC+ACID'>UL4</scene></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=4tqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tqn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tqn RCSB], [http://www.ebi.ac.uk/pdbsum/4tqn PDBsum]</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=4tqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tqn OCA], [http://pdbe.org/4tqn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tqn RCSB], [http://www.ebi.ac.uk/pdbsum/4tqn PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4tqn" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4tqn

From Proteopedia

Revision as of 19:47, 9 March 2016

Crystal structure of the bromodomain of human CREBBP in complex with UL04

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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