Abstract
Antibody fragments have long been used as chaperones in crystallography, but have more recently been applied to the definition of biologically relevant conformations among the dynamic ensemble of target protein conformational sampling. This review charts the progress being made in understanding function in the context of structure using this approach, and highlights new opportunities for drug discovery.
Highlights
Antibody fragments continue to be widely used as essential tools in crystallography, but it has become clear that their utility extends beyond the properties outlined above to encompass definition of specific, biologically relevant conformations of target proteins, enabling all-important connections to be established between structure, function and clinical validation
By 2009, firm links were starting to be made between Fab fragments acting as chaperones in stabilising structures in crystallography and their utility in defining clinically important conformations of proteins; for example the first crystal structure of the physiologically relevant closed conformation of the proton-activated, voltage-modulated K+ channel KcsA, enabled by a synthetic Fab fragment, was published at this time [15]
The overall structure of the GPCR was remarkably similar to the nanobody-stabilised version, validating the use of antibody fragments, with functional similarity to known binding partners, in defining specific, biologically relevant conformations of target proteins
Summary
Antibody fragments have been used as chaperones to aid crystallization and enable structure-determination of target proteins for many years [1], from the first application of:. Antibody fragments continue to be widely used as essential tools in crystallography, but it has become clear that their utility extends beyond the properties outlined above to encompass definition of specific, biologically relevant conformations of target proteins, enabling all-important connections to be established between structure, function and clinical validation. In this new role, broad application of antibody fragments as tools to ‘lock out’ validated conformations of target proteins is leading to exciting opportunities in drug discovery from Neuroscience to Immunology, and the pioneering work of Brian. Kobilka on the β2 adrenergic receptor and Jan Steyaert with single domain VHH (nanobody) antibody technology deserves special mention
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