title: NMR-Based Determination of the 3D Structure of the Ligand-Protein Interaction Site without Protein Resonance Assignment.
abstract: Molecular replacement in X-ray crystallography is the prime method for establishing structure-activity relationships of pharmaceutically relevant molecules. Such an approach is not available for NMR. Here, we establish a comparable method, called NMR molecular replacement (NMR(2)). The method requires experimentally measured ligand intramolecular NOEs and ligand-protein intermolecular NOEs as well as a previously known receptor structure or model. Our findings demonstrate that NMR(2) may open a new avenue for the fast and robust determination of the interaction site of ligand-protein complexes at atomic resolution.
authors.affiliation: ETH Zürich , Laboratory of Physical Chemistry, HCI F217, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Orts
authors.affiliation: ETH Zürich , Laboratory of Physical Chemistry, HCI F217, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.
authors.forename: Marielle Aulikki
authors.initials: MA
authors.lastname: Wälti
authors.affiliation: Swiss Light Source, Paul Scherrer Institute , CH-5232 Villigen, Switzerland.
authors.forename: May
authors.initials: M
authors.lastname: Marsh
authors.affiliation: Swiss Light Source, Paul Scherrer Institute , CH-5232 Villigen, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Vera
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG , CH-4002 Basel, Switzerland.
authors.forename: Alvar D
authors.initials: AD
authors.lastname: Gossert
authors.affiliation: ETH Zürich , Laboratory of Physical Chemistry, HCI F217, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.|Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, and Frankfurt Institute of Advanced Studies, Goethe University Frankfurt am Main , Frankfurt am Main 60323, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Güntert
authors.affiliation: ETH Zürich , Laboratory of Physical Chemistry, HCI F217, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011506:Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011506:Proteins