4BKS

von Hippel Lindau protein:ElonginB:ElonginC complex, in complex with (2S,4R)-1-ethanoyl-N-[[4-(1,3-oxazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide

4BKS の概要

• エントリーDOI: 10.2210/pdb4bks/pdb
• 関連するPDBエントリー: 4BKT
• 分子名称: TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 2, TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 1, VON HIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR, ... (7 entities in total)
• 機能のキーワード: protein transport, e3 ubiquitin ligase, fragment based drug discovery
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Nucleus (Probable): Q15370 Q15369 Q15370; Isoform 1: Cytoplasm. Isoform 3: Cytoplasm: P40337
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 167760.63

構造登録者

Van Molle, I.,Dias, D.M.,Baud, M.,Galdeano, C.,Geraldes, C.F.G.C.,Ciulli, A. (登録日: 2013-04-29, 公開日: 2013-11-27, 最終更新日: 2024-11-13)

主引用文献

Dias, D.M.,Van Molle, I.,Baud, M.G.J.,Galdeano, C.,Geraldes, C.F.G.C.,Ciulli, A.
Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?
Acs Med.Chem.Lett., 5:23-, 2014

PubMed Abstract: Modulation of protein-protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel-Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α). Careful triaging allowed rescuing weak but specific binding of fragments that would otherwise escape detection at this PPI. Further structural information provided by saturation transfer difference (STD) group epitope mapping, protein-based NMR, competitive isothermal titration calorimetry (ITC), and X-ray crystallography confirmed the binding mode of the rescued fragments. Our findings have important implications for PPI druggability assessment by fragment screening as they reveal an accessible threshold for fragment detection and validation.

PubMed: 24436777
DOI: 10.1021/ML400296C

実験手法

X-RAY DIFFRACTION (2.2 Å)