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PDBsum entry 5ek9
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Transcription
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PDB id
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5ek9
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PDB id:
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| Name: |
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Transcription
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Title:
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Crystal structure of the second bromodomain of human brd2 in complex with a tetrahydroquinoline inhibitor
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Structure:
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Bromodomain-containing protein 2. Chain: a, b. Fragment: unp residues 344-455. Synonym: o27.1.1,really interesting new gene 3 protein. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: brd2, kiaa9001, ring3. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.08Å
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R-factor:
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0.184
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R-free:
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0.223
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Authors:
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C.Tallant,P.J.Slavish,P.Siejka,N.Bharatham,W.R.Shadrick,S.Chai, B.M.Young,V.A.Boyd,C.Heroven,S.Picaud,O.Fedorov,T.Chen,R.E.Lee, R.K.Guy,A.A.Shelat,F.Von Delft,C.H.Arrowsmith,A.M.Edwards,C.Bountra, S.Knapp,Structural Genomics Consortium (Sgc)
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Key ref:
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W.R.Shadrick
et al.
(2018).
Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors.
Bioorg Med Chem,
26,
25-36.
PubMed id:
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Date:
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03-Nov-15
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Release date:
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16-Nov-16
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PROCHECK
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Headers
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References
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P25440
(BRD2_HUMAN) -
Bromodomain-containing protein 2 from Homo sapiens
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Seq:
Struc:
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801 a.a.
107 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Bioorg Med Chem
26:25-36
(2018)
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PubMed id:
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Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors.
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W.R.Shadrick,
P.J.Slavish,
S.C.Chai,
B.Waddell,
M.Connelly,
J.A.Low,
C.Tallant,
B.M.Young,
N.Bharatham,
S.Knapp,
V.A.Boyd,
M.Morfouace,
M.F.Roussel,
T.Chen,
R.E.Lee,
R.Kiplin Guy,
A.A.Shelat,
P.M.Potter.
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ABSTRACT
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Within the last decade, the Bromodomain and Extra-Terminal domain family (BET)
of proteins have emerged as promising drug targets in diverse clinical
indications including oncology, auto-immune disease, heart failure, and male
contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and
BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains
(BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and
appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at
five positions near the substrate binding pocket: the variation in the ZA
channel induces different water networks nearby. We designed a set of congeneric
2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially
engage bound waters in the ZA channel with the goal of achieving bromodomain
selectivity. SJ830599 (9) showed modest, but consistent, selectivity for
BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of
all THQ analogs in our study to either of the two bromodomains was enthalpy
driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy
and was entirely driven by enthalpy, consistent with significant restriction of
conformational flexibility and/or engagement with bound waters.
Co-crystallography studies confirmed that 9 did indeed stabilize a
water-mediated hydrogen bond network. Finally, we report that 9 retained
cytotoxicity against several pediatric cancer cell lines with
EC50values comparable to BET inhibitor (BETi) clinical candidates.
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Links
