Laying the foundations for three-dimensionalprotein structure determination in solution byNMR, developing innovative approaches for extendingNMR to larger and more complex systems, and usingNMR to uncover invisible states of proteins
"Clore pioneered the development of NMR for determining three-dimensional structures of biological macromolecules and has consistently extended the frontiers of NMR to ever more complex systems. His work on the development of paramagnetic and other relaxation-based NMR experiments to detect and visualize transient, rare states of macromolecules, invisible to conventional structural and biophysical techniques, has shed unique insights into how macromolecules efficiently locate their binding partners, provided the first atomic view of the dynamic amyloid Aß assembly process from disordered peptides into protofibrils, and directly demonstrated that the apo state of the chaperonin GroEL possesses intrinsic foldase/unfoldase activities."[5]
Clore played a pivotal role in the development of three- and four-dimensional NMR spectroscopy,[21] the use ofresidual dipolar couplings for structure determination,[22] the development of simulated annealing and restrained molecular dynamics for three-dimensional protein and nucleic acid structure determination,[23] the solution NMR structure determination of large protein complexes,[24] the development of the combined use of NMR andsmall-angle X-ray scattering in solution structure determination,[25] and the analysis and characterization ofprotein dynamics by NMR.[26] Clore's work on complexes of all the cytoplasmic components of the bacterialphosphotransferase system (PTS) led to significant insights into howsignal transduction proteins recognize multiple, structurally dissimilar partners by generating similar binding surfaces from completely different structural elements and exploiting side chain conformational plasticity.[24] Clore is also one of the main authors of the very widely usedXPLOR-NIH NMR structure determination program[27]
Detection and visualization of excited and sparsely populated states
Clore's recent work has focused on developing new NMR methods (such asparamagnetic relaxation enhancement, dark state exchange saturation transfer spectroscopy and lifetime line broadening) to detect, characterize and visualize the structure and dynamics of sparsely populated states of macromolecules, which are important in macromolecular interactions but invisible to conventional structural and biophysical techniques.[28] Examples of include the direct demonstration of rotation-coupled sliding and intermolecular translocation as mechanisms whereby sequence-specific DNA binding proteins locate their target site(s) within an overwhelming sea of non-specific DNA sequences;[29] the detection, visualization and characterization of encounter complexes in protein-protein association;[30] the analysis of the synergistic effects of conformational selection and induced fit in protein-ligand interactions;[31] and the uncovering of "dark", spectroscopically invisible states in interactions of NMR-visible proteins and polypeptides (including intrinsically disordered states) with very large megadalton macromolecular assemblies.[32] The latter includes an atomic-resolution view of the dynamics of theamyloid-β aggregation process.[33] and the demonstration of intrinsic unfoldase/foldase activity of the macromolecular machine GroEL.[34] These various techniques have also been used to uncover the kinetic pathway of pre-nucleation transient oligomerization events and associated structures involving the protein encoded by huntingtin exon-1, which may provide a potential avenue for therapeutic intervention in Huntington's disease, a fatal autosomal dominant, neurodegenerative condition.[35][36]
2012:Biochemical Society 2013 Centenary Award (previously known as the Jubilee Medal) and Sir Frederick Gowland Hopkins Memorial Lecture (U.K.)[47][48]
^"New Members and Foreign Associates of the National Academy of Sciences: G. Marius Clore, Gregory C. Fu, Sir J. Fraser Stoddart, Ei-ichi Negishi".Angewandte Chemie International Edition.53 (26): 6598. 2014.Bibcode:2014ACIE...53.6598..doi:10.1002/anie.201405510.
