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PDBsum entry 4w9f
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104 a.a.
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87 a.a.
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141 a.a.
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99 a.a.
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87 a.a.
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87 a.a.
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87 a.a.
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133 a.a.
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PDB id:
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Ligase
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Title:
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Pvhl:elob:eloc in complex with (2s,4r)-1-(3,3-dimethylbutanoyl)-4- hydroxy-n-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 5)
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Structure:
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Transcription elongation factor b polypeptide 2. Chain: a, d, g, j. Synonym: elongin 18 kda subunit,elongin-b,elob,RNA polymerase ii transcription factor siii subunit b,siii p18. Engineered: yes. Transcription elongation factor b polypeptide 1. Chain: b, e, h, k. Synonym: elongin 15 kda subunit,elongin-c,eloc,RNA polymerase ii transcription factor siii subunit c,siii p15.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: tceb2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: tceb1. Gene: vhl.
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Resolution:
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2.10Å
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R-factor:
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0.206
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R-free:
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0.229
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Authors:
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I.Van Molle,S.Hewitt,C.Galdeano,M.S.Gadd,A.Ciulli
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Key ref:
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C.Galdeano
et al.
(2014).
Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.
J Med Chem,
57,
8657-8663.
PubMed id:
DOI:
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Date:
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27-Aug-14
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Release date:
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10-Sep-14
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PROCHECK
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Headers
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References
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Q15370
(ELOB_HUMAN) -
Elongin-B from Homo sapiens
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Seq:
Struc:
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118 a.a.
104 a.a.*
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Q15369
(ELOC_HUMAN) -
Elongin-C from Homo sapiens
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Seq:
Struc:
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112 a.a.
87 a.a.*
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P40337
(VHL_HUMAN) -
von Hippel-Lindau disease tumor suppressor from Homo sapiens
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Seq:
Struc:
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213 a.a.
141 a.a.*
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Q15370
(ELOB_HUMAN) -
Elongin-B from Homo sapiens
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Seq:
Struc:
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118 a.a.
99 a.a.*
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Q15369
(ELOC_HUMAN) -
Elongin-C from Homo sapiens
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Seq:
Struc:
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112 a.a.
87 a.a.*
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Q15369
(ELOC_HUMAN) -
Elongin-C from Homo sapiens
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Seq:
Struc:
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112 a.a.
87 a.a.
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DOI no:
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J Med Chem
57:8657-8663
(2014)
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PubMed id:
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Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.
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C.Galdeano,
M.S.Gadd,
P.Soares,
S.Scaffidi,
I.Van Molle,
I.Birced,
S.Hewitt,
D.M.Dias,
A.Ciulli.
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ABSTRACT
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E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system,
however, the development of small-molecule ligands has been rewarded with
limited success. The von Hippel-Lindau protein (pVHL) is the substrate
recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation.
We recently reported inhibitors of the pVHL:HIF-1α interaction, however they
exhibited moderate potency. Herein, we report the design and optimization,
guided by X-ray crystal structures, of a ligand series with nanomolar binding
affinities.
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