4ogj: Difference between revisions
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==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348== | ==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348== | ||
<StructureSection load='4ogj' size='340' side='right' caption='[[4ogj]], [[Resolution|resolution]] 1.65Å' scene=''> | <StructureSection load='4ogj' size='340' side='right'caption='[[4ogj]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ogj]] 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=4OGJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OGJ FirstGlance]. <br> | <table><tr><td colspan='2'>[[4ogj]] 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=4OGJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OGJ FirstGlance]. <br> | ||
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</div> | </div> | ||
<div class="pdbe-citations 4ogj" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4ogj" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Arrowsmith, C H]] | [[Category: Arrowsmith, C H]] | ||
[[Category: Bountra, C]] | [[Category: Bountra, C]] | ||
Revision as of 07:33, 13 February 2020
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348
Structural highlights
Disease[BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2] Function[BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedConcomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.,Ciceri P, Muller S, O'Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, Knapp S Nat Chem Biol. 2014 Apr;10(4):305-12. doi: 10.1038/nchembio.1471. Epub 2014 Mar, 2. PMID:24584101[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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