6XV7

CRYSTAL STRUCTURE OF BRD4-BD1 WITH COMPOUND 2

Summary for 6XV7

• Entry DOI: 10.2210/pdb6xv7/pdb
• Related: 6XUZ 6XV3
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, ~{N}-[[3,4-bis(fluoranyl)phenyl]methyl]-~{N},3-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine, ... (4 entities in total)
• Functional Keywords: bromodomain, inhibitor, complex, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15574.87

Authors

Bader, G.,Kessler, D.,Wolkerstorfer, B. (deposition date: 2020-01-21, release date: 2020-07-08, Last modification date: 2024-01-24)

Primary citation

Platzer, G.,Mayer, M.,Beier, A.,Bruschweiler, S.,Fuchs, J.E.,Engelhardt, H.,Geist, L.,Bader, G.,Schorghuber, J.,Lichtenecker, R.,Wolkerstorfer, B.,Kessler, D.,McConnell, D.B.,Konrat, R.
PI by NMR: Probing CH-pi Interactions in Protein-Ligand Complexes by NMR Spectroscopy.
Angew.Chem.Int.Ed.Engl., 59:14861-14868, 2020

PubMed Abstract: While CH-π interactions with target proteins are crucial determinants for the affinity of arguably every drug molecule, no method exists to directly measure the strength of individual CH-π interactions in drug-protein complexes. Herein, we present a fast and reliable methodology called PI (π interactions) by NMR, which can differentiate the strength of protein-ligand CH-π interactions in solution. By combining selective amino-acid side-chain labeling with H- C NMR, we are able to identify specific protein protons of side-chains engaged in CH-π interactions with aromatic ring systems of a ligand, based solely on H chemical-shift values of the interacting protein aromatic ring protons. The information encoded in the chemical shifts induced by such interactions serves as a proxy for the strength of each individual CH-π interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual π interactions rather than averaged measures of all interactions.

PubMed: 32421895
DOI: 10.1002/anie.202003732

Experimental method

X-RAY DIFFRACTION (1.668 Å)