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PDBsum entry 4z6h
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Transcription
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PDB id
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4z6h
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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 brd9 bromodomain in complex with a valerolactam quinolone ligand
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Structure:
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Bromodomain-containing protein 9. Chain: a, b. Fragment: unp residues 14-134. Synonym: rhabdomyosarcoma antigen mu-rms-40.8. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: brd9, unq3040/pro9856. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.80Å
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R-factor:
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0.223
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R-free:
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0.271
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Authors:
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C.Tallant,Structural Genomics Consortium (Sgc),P.G.K.Clark, L.C.C.Vieira,T.Krojer,G.Nunez-Alonso,S.Picaud,O.Fedorov,D.J.Dixon, F.Von Delft,C.H.Arrowsmith,A.M.Edwards,C.Bountra,P.E.Brennan,S.Knapp
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Key ref:
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P.G.Clark
et al.
(2015).
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.
Angew Chem Int Ed Engl,
54,
6217-6221.
PubMed id:
DOI:
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Date:
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05-Apr-15
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Release date:
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20-May-15
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PROCHECK
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Headers
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References
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Q9H8M2
(BRD9_HUMAN) -
Bromodomain-containing protein 9 from Homo sapiens
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Seq:
Struc:
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597 a.a.
113 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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*
PDB and UniProt seqs differ
at 10 residue positions (black
crosses)
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DOI no:
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Angew Chem Int Ed Engl
54:6217-6221
(2015)
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PubMed id:
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LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.
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P.G.Clark,
L.C.Vieira,
C.Tallant,
O.Fedorov,
D.C.Singleton,
C.M.Rogers,
O.P.Monteiro,
J.M.Bennett,
R.Baronio,
S.Müller,
D.L.Daniels,
J.Méndez,
S.Knapp,
P.E.Brennan,
D.J.Dixon.
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ABSTRACT
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The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF
chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for
BRD7/9 has been reported despite its potential value as a biological tool or as
a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported
as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains.
Development of LP99 from a fragment hit was expedited through balancing
structure-based inhibitor design and biophysical characterization against
tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization
cascade processes allowed for early structure-activity relationship studies
whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the
synthesis of the lead scaffold in enantioenriched form and on scale. This
epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to
acetylated histones in vitro and in cells. Moreover, LP99 was used to
demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine
secretion.
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