4BKT

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

Summary for 4BKT

• Entry DOI: 10.2210/pdb4bkt/pdb
• Related: 4BKS
• Descriptor: TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 2, TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 1, VON HIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR, ... (7 entities in total)
• Functional Keywords: protein transport, ligase, fragment based drug discovery
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus : Q15370 Q15369; Isoform 1: Cytoplasm. Isoform 3: Cytoplasm: P40337
• Total number of polymer chains: 12
• Total formula weight: 167924.57

Authors

Van Molle, I.,Dias, D.M.,Baud, M.,Galdeano, C.,Geraldes, C.F.G.C.,Ciulli, A. (deposition date: 2013-04-29, release date: 2013-11-27, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)