6FMI

pVHL:EloB:EloC in complex with N-((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamothioyl) pyrrolidin-1-yl)-1-oxopropan-2-yl)acetamide (ligand 2)

Summary for 6FMI

• Entry DOI: 10.2210/pdb6fmi/pdb
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (5 entities in total)
• Functional Keywords: protein complex, ubiquitin ligase, hypoxia inducible factor, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 82231.22

Authors

Soares, P.,Lucas, X.,Ciulli, A. (deposition date: 2018-01-31, release date: 2018-04-11, Last modification date: 2018-06-20)

Primary citation

Soares, P.,Lucas, X.,Ciulli, A.
Thioamide substitution to probe the hydroxyproline recognition of VHL ligands.
Bioorg. Med. Chem., 26:2992-2995, 2018

PubMed Abstract: Thioamide substitution influences hydrogen bond and n → π interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central hydroxyproline moiety, and characterize their binding by fluorescence polarization, isothermal titration calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved binding mode, the substitution pattern had a pronounced impact on the ligand affinities. Together the results underscore the role of hydrogen bond and n → π interactions in fine tuning hydroxyproline recognition by VHL.

PubMed: 29650462
DOI: 10.1016/j.bmc.2018.03.034

Experimental method

X-RAY DIFFRACTION (2.8 Å)