title: How much NMR data is required to determine a protein-ligand complex structure?
abstract: Here we present an NMR-based approach to solving protein-ligand structures. The procedure is guided by biophysical, biochemical, or knowledge-based data. The structures are mainly derived from ligand-induced chemical-shift perturbations (CSP) induced in the resonances of the protein and ligand-detected saturated transfer difference signals between ligands and selectively labeled proteins (SOS-NMR). Accuracy, as judged by comparison with X-ray results, depends on the nature and completeness of the experimental data. An experimental protocol is proposed that starts with calculations that make use of readily available chemical-shift perturbations as experimental constraints. If necessary, more sophisticated experimental results have to be added to improve the accuracy of the protein-ligand complex structure. The criteria for evaluation and selection of meaningful complex structures are discussed. These are exemplified for three complexes, and we show that the approach bridges the gap between theoretical docking approaches and complex NMR schemes for determining protein-ligand complexes; especially for relatively weak binders that do not lead to intermolecular NOEs.
authors: Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe Universität Frankfurt, Marie Curie Strasse 11, 60439 Frankfurt am Main, Germany.
authors: Ulrich
authors: U
authors: Schieborr
authors: Martin
authors: M
authors: Vogtherr
authors: Bettina
authors: B
authors: Elshorst
authors: Marco
authors: M
authors: Betz
authors: Susanne
authors: S
authors: Grimme
authors: Barbara
authors: B
authors: Pescatore
authors: Thomas
authors: T
authors: Langer
authors: Krishna
authors: K
authors: Saxena
authors: Harald
authors: H
authors: Schwalbe
mesh_terms: D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases