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PDBsum entry 6fdk
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References listed in PDB file
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Key reference
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Title
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Structural basis of substrate recognition and covalent inhibition of cdu1 from chlamydia trachomatis.
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Authors
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Y.A.Ramirez,
T.B.Adler,
E.Altmann,
T.Klemm,
C.Tiesmeyer,
F.Sauer,
S.G.Kathman,
A.V.Statsyuk,
C.Sotriffer,
C.Kisker.
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Ref.
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ChemMedChem, 2018,
13,
2014-2023.
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PubMed id
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Abstract
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Based on the similarity between the active sites of the deubiquitylating and
deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionarily related protease
adenain, a target-hopping screening approach on a focused set of adenain
inhibitors was investigated. The cyanopyrimidine-based inhibitors identified
represent the first active-site-directed small-molecule inhibitors of Cdu1.
High-resolution crystal structures of Cdu1 in complex with two covalently bound
cyanopyrimidines, as well as with its substrate ubiquitin, were obtained. These
structural data were complemented by enzymatic assays and covalent docking
studies to provide insight into the substrate recognition of Cdu1, active-site
pocket flexibility and potential hotspots for ligand interaction. Combined,
these data provide a strong basis for future structure-guided medicinal
chemistry optimization of this cyanopyrimidine scaffold into more potent and
selective Cdu1 inhibitors.
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