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PDBsum entry 5urm
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Hydrolase/hydrolase inhibitor
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PDB id
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5urm
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of human brr2 in complex with t-1206548
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Structure:
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U5 small nuclear ribonucleoprotein 200 kda helicase. Chain: a, b. Fragment: unp residues 395-2129. Synonym: activating signal cointegrator 1 complex subunit 3-like 1, brr2 homolog,u5 snrnp-specific 200 kda protein,u5-200kd. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: snrnp200, ascc3l1, helic2, kiaa0788. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.80Å
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R-factor:
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0.215
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R-free:
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0.260
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Authors:
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M.G.Klein,R.Tjhen,L.Qin
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Key ref:
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M.Iwatani-Yoshihara
et al.
(2017).
Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2.
J Med Chem,
60,
5759-5771.
PubMed id:
DOI:
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Date:
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11-Feb-17
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Release date:
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19-Jul-17
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PROCHECK
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Headers
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References
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O75643
(U520_HUMAN) -
U5 small nuclear ribonucleoprotein 200 kDa helicase from Homo sapiens
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Seq:
Struc:
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2136 a.a.
1718 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.3.6.4.13
- Rna helicase.
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Reaction:
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ATP + H2O = ADP + phosphate + H+
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ATP
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+
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H2O
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=
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ADP
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+
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phosphate
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
60:5759-5771
(2017)
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PubMed id:
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Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2.
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M.Iwatani-Yoshihara,
M.Ito,
M.G.Klein,
T.Yamamoto,
K.Yonemori,
T.Tanaka,
M.Miwa,
D.Morishita,
S.Endo,
R.Tjhen,
L.Qin,
A.Nakanishi,
H.Maezaki,
T.Kawamoto.
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ABSTRACT
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Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential
component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6
RNA duplex, which is a critical step for spliceosomal activation. An HTS
campaign using an RNA-dependent ATPase assay and initial SAR study identified
two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds
to an unexpected allosteric site between the C-terminal and the N-terminal
helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal
cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more
Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using
SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9
with helicase inhibitory activity. Our findings demonstrate an effective
strategy to explore selective inhibitors for helicases, and 9 could be a
promising starting point for exploring molecular probes to elucidate biological
functions and the therapeutic relevance of Brr2.
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Links
