We wholly support exploiting the complementarity of NMR spectroscopy, X-ray crystallography (XRS) and cryoEM, as well as of lower resolution structural methodologies, such as small angle scattering (SAS), FRET and others, to yield ground-breaking discoveries in molecular science.
With the significant advances in cryoEM and the automatisation of routine XRS, biomolecular NMR has gained even more relevance in its unique areas of strength:
- High molecular weight complexes: Methyl TROSY and 15N,13C-direct-detection experiments allow molecular species as large as 1 MDa to be interrogated by solution NMR. In this remit, NMR has unique capabilities to study (1) transient interactions, which lie at the heart of several important enzymatic processes; (2) complexes involving dynamical regions, subject to regulation through the environment and binding partners; (3) complexes existing in multiple conformations. References
- Analysis of disorder: the paradigm of the (folded) structure–function relationship has been challenged by a revolutionary paper (Borgia et al. Nature 2018) describing a functional complex between two intrinsically unfolded proteins, which both remain disordered upon interaction. Because of their abundance in the eukaryotic proteome, disordered protein motifs will indisputably be protagonists in structural biology, and NMR is the only technique able to characterize them at atomic-resolution. New methods must be developed to go beyond the conventional structure determination process, as the concept of single, well-defined structures is replaced by a large but biased ensemble of transient conformations. References
- RNA structure and dynamics: RNA biology has gained immense importance in the past 3 decades, following the discovery of the pivotal regulatory role of RNA in cellular processes, including those related to diseases (e.g. infection, cancer, neuropathologies). Structural biology of RNA is challenging due to the conformational plasticity of the RNA. Solid-state NMR is unique in that it guarantees access to atomic resolution structural information with no inherent limitation of molecular weight; consequently, it can adopt an irreplaceable role in RNA structural biology. The facility offers world-wide unique expertise in ssNMR applied to RNA, as well as in RNA structure and dynamics by solution NMR. References
- Conformational dynamics and function: Besides solving new biomolecular structures, NMR is used to reveal the molecular motions that underline function. For example, NMR has revealed that the access to multiple conformational states is critical for enzymatic function and the kinetics of transitions between these states determines the regulation of enzymatic activities. For regulatory protein domains, NMR-derived insights into allosteric effects and conformational dynamics have achieved a better understanding of protein–ligand interactions in drug-discovery. NMR is even sensitive to the presence of highly transient states and can reveal important insights into their structure that are not accessible by any other method.
Our structural biology users are funded by the BBSRC, Cancer Research UK, EU, MRC, Wellcome Trust and other funding agencies.