SOS-NMR: a saturation transfer NMR-based method for determining the structures of protein-ligand complexes.
An NMR-based alternative to traditional X-ray crystallography and NMR methods for structure-based drug design is described that enables the structure determination of ligands complexed to virtually any biomolecular target regardless of size, composition, or oligomeric state. The method utilizes saturation transfer difference (STD) NMR spectroscopy performed on a ligand complexed to a series of target samples that have been deuterated everywhere except for specific amino acid types. In this way, the amino acid composition of the ligand-binding site can be defined, and, given the three-dimensional structure of the protein target, the three-dimensional structure of the protein-ligand complex can be determined. Unlike earlier NMR methods for solving the structures of protein-ligand complexes, no protein resonance assignments are necessary. Thus, the approach has broad potential applications--especially in cases where X-ray crystallography and traditional NMR methods have failed to produce structural data. The method is called SOS-NMR for structural information using Overhauser effects and selective labeling and is validated on two protein-ligand complexes: FKBP complexed to 2-(3'-pyridyl)-benzimidazole and MurA complexed to uridine diphosphate N-acetylglucosamine.
Hajduk
Philip J
PJ
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA. philip.hajduk@abbott.com
Mack
Jamey C
JC
Olejniczak
Edward T
ET
Park
Chang
C
Dandliker
Peter J
PJ
Beutel
Bruce A
BA
D019883:Alkyl and Aryl Transferases / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011487:Protein Conformation; D022021:Tacrolimus Binding Proteins / Q000737:chemistry*; D013816:Thermodynamics; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000737:chemistry
D001562:Benzimidazoles; D014537:Uridine Diphosphate N-Acetylglucosamine; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase; D022021:Tacrolimus Binding Proteins