Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Structure-based drug design traditionally uses static protein structures.
• Protein dynamics are increasingly recognized as critical for understanding receptor-ligand interactions but are poorly understood and modeled.
• Lack of experimental data on dynamic receptor-ligand complexes hinders progress.

Purpose of the Study:

• To provide high-resolution structural and dynamic details of a receptor-small molecule complex.
• To investigate the role of protein dynamics in drug binding.
• To establish a benchmark for modeling protein dynamics in drug design.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy, specifically Carr-Purcell-Meiboom-Gill relaxation dispersion experiments and NOEs.
• X-ray crystallography.
• Integrated analysis of NMR and X-ray data.

Main Results:

• Detailed characterization of ~1 ms timescale conformational dynamics in a receptor-ligand complex.
• Identified internal switching motions of the inhibitor as the driver of large conformational dynamics in Escherichia coli dihydrofolate reductase.
• The crystal structure was found to incorporate key features of a high-energy protein-ligand conformation.

Conclusions:

• Accurate, structure-resolved dynamics of protein-ligand complexes are achievable and essential.
• This work provides a valuable benchmark for computational modeling of dynamics and binding affinity prediction.
• Understanding protein dynamics is critical for advancing structure-based drug design.