Abstract
Structural characterization of complexes is crucial for a better understanding of biological processes and structure-based drug design. However, many protein–ligand structures are not solvable by X-ray crystallography, for example those with low affinity binders or dynamic binding sites. Such complexes are usually targeted by solution-state NMR spectroscopy. Unfortunately, structure calculation by NMR is very time consuming since all atoms in the complex need to be assigned to their respective chemical shifts. To circumvent this problem, we recently developed the Nuclear Magnetic Resonance Molecular Replacement (NMR2) method. NMR2 very quickly provides the complex structure of a binding pocket as measured by solution-state NMR. NMR2 circumvents the assignment of the protein by using previously determined structures and therefore speeds up the whole process from a couple of months to a couple of days. Here, we recall the main aspects of the method, show how to apply it, discuss its advantages over other methods and outline its limitations and future directions.
Highlights
We recently developed the Nuclear Magnetic Resonance Molecular Replacement (NMR2) method
Various methods have been developed in order to derive protein–ligand complex structures faster than with the classical NMR structure calculation protocol, but these methods mostly rely on a preliminary docking step rather than on experimentally driven calculations
It is a highly efficient way to determine protein/ligand complex structures, without the need to perform the tedious protein resonance assignment, and structures can be calculated within a couple of days
Summary
Most biological processes rely on highly specific protein–protein or protein–ligand inter-molecular interactions Understanding and manipulating these interactions is the ultimate goal of drug design. Drug discovery commonly starts by screening large libraries of molecules or fragments against a carefully selected drug target, with identified binders further optimized by molecular refinement or fragment-based design approaches. This approach was enabled by advances in biology (e.g., biochemistry, molecular biology and genomics) that drive the search for better drug targets. Progress in chemistry and bioinformatics allowed for the synthesis and screening of enormous compound libraries These methods, Magnetochemistry 2018, 4, 12 search for better drug targets.
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