Dr Brian Smith
- Senior Lecturer (Institute of Molecular Cell & Systems Biology)
- Affiliate (MVLS Administration)
- Associate (School of Life Sciences)
Nuclear Magnetic Resonance spectroscopy is the only technique that can determine high-resolution structures of macromolecules in solution, and can also probe molecular motion and intermolecular interactions. Brian's group use the technique to study the structures and functions of proteins and nucleic acids involved in interesting processes in a variety of systems. They are also interested in developing NMR methodology. They have a recently updated 600 MHz NMR spectrometer (2013) equipped with a cryoprobe. High-resolution molecular structures are normally determined in vitro, but Brian was part of the team that solved the first structure of a protein inside living cells. We collaborate widely with other biologists and chemists and currently have particular interests in the biophysics and application of natural surfactant proteins, in fatty acid binding proteins from nematode parasites, in the structural basis of epigenetic gene regulation, in the regulation of viral life cycles, in the molecular basis of endotoxin sensing, and in ultraviolet light perception by plants.
Natural surfactant proteins
Surfactants are typically small molecule amphiphiles, but these are typically disruptive to cells. Proteins that act as cell compatible surfactants have arisen independently several times in evolution. Brian's group study ranaspumins found in the foam nests of tropical frogs and the salivary and airway surfactants, equine latherin and human SPLUNC1. The conformational transition that these proteins undergo to convert to their surface active forms sets them apart from other classes of protein surfactants. The group are also exploring biotechnological applications of surfactant proteins.
Collaborators: Prof Malcolm Kennedy, Dr Mathis Riehle, Prof Cait MacPhee (University of Edinburgh), Prof Matt Redinbo (UNC Chapel Hill, USA).
Figure 1 Three views of a cartoon of the structure of the solution form of the surfactant protein latherin showing the locations of the many leucine (yellow) and isoleucine (orange) residues as spheres. (PDB:3ZPM)
Novel fatty acid binding proteins
Brian's group studies the structures and ligand binding properties of novel fatty acid binding proteins from parasites. Parasitic nematodes are responsible for some of the most widespread and pernicious diseases in the developing world as well as causing losses in agriculture. The parasites must scavenge metabolites, including fatty acids and retinoids, from their hosts and maintain a reservoir of fatty acid binding proteins in their pseudocoelemic fluid. Brian's group have determined the structures of nematode polyprotein antigen subunits (NPAs) and fatty acid and retinoid binding proteins (FARs) and more typical FABP proteins and are examining their lipid binding in detail.
Collaborators: Prof Malcolm Kennedy, Prof Betina Córsico (INIBIOLP, Argentina).
Figure 2 Fatty acid binding by Na-FAR-1 followed by 15N HSQC NMR spectra. The peaks arising from the amide NH of each amino acid residue are seen to jump from one position to another as oleate is titrated into the protein indicating that it can bind multiple ligands, adopting a distinct conformation in each case.
Structural basis of epigenetic gene regulation
Epigenetics describes heritable changes in gene expression that do not involve an alteration of the DNA sequence. For example, as a complex organism develops, its cells differentiate from stem cells into specialised cell types in which groups of genes are down regulated in a heritable fashion. This down regulation requires specialised forms of chromatin (DNA and the proteins that package it) that prevents the transcription machinery from gaining access to the genes. Molecular signals including DNA methylation and modification of histone tails are key to these processes. Brian's group study the structures of the proteins that recognise and interpret these modifications.
Ultraviolet light perception
UVR8, the protein through which plants sense ultraviolet light, is unusual in using tryptophan residues, rather than an additional chromophore. The group are trying to understand the mechanism of UV perception and the conformational changes in the protein that effect downstream signalling.
Collaborators: Prof Gareth Jenkins, Prof John Christie.
Grants and Awards listed are those received whilst working with the University of Glasgow.
- Co-ordinated Photoreceptor Engineering for Improved Biomass Production
2020 - 2023
- Role of reversible modification of methionine residues in the regulation of protein function
2020 - 2023
- Scottish High-Field NMR Facility
2018 - 2021
- A novel mechanism of protein uptake in Gram-negative bacteria
2014 - 2018
- Assessing the predictive value of quantitative high-throughput NMR metabolomic analysis for CVD events in a major study of diabetes: ADVANCE
2013 - 2016
- How does the plant UV-B photoreceptor UVR8 initiate signalling?
2013 - 2016
- Final structure refinement and functional analysis of Na-FAR-1
2012 - 2012
- Structure determination and functional analysis through Nuclear Magnetic Resonance
2012 - 2012
- The application of a high-throughput NMR metabolomics system to the study of insulin resistance (ISSF Catalyst)
2011 - 2014
- Interaction between the essential replication factor TopBP1 and human papillomavirus 16 E1: a novel antiviral target
2011 - 2015
- Identification of small molecule activators of EPAC1 to serve as novel anti-inflamatory agents in vascular endothelial cells
2011 - 2012
- Quest for the Holy Grail of plant photobiology: a UV-B photoreceptor
2010 - 2014
- Structural and biophysical analysis of novel lipid binding proteins from parasitic helminths
2008 - 2012
- The solution structures of newly discovered natural inhibitors of cystine peptidases from eukaryotic and bacterial pathogens
2004 - 2008
- Toward Understanding the structural basis of molecular recognition by methylated DNA binding proteins
2004 - 2005
- Establishment of high field NMR facility
2003 - 2006
Grant Advisory Board
- 2001 - 2009: BBSRC - Member of Executive Committee of CCPN (A Collaborative Computing Project for the NMR Community). Committee Chair 2007-2009
Invited International Presentations
- 2013: La Plata, Argentina - 8th International Conference on Lipid Binding Proteins: Session chair, Structural Biology of LBPs; Invited speaker, "Structures and ligand binding of all-alpha-helical lipid binding proteins from nematodes"
- 2009: Ambleside, England - Meeting Chair, 9th CCPN Meeting; speaker, "An overview of fast NMR methods and their practical aspects"
- 2008: Ambleside, England - Meeting Chair 8th CCPN Meeting
- 2007: Tokyo, Japan - Invited speaker, Symposium: "Application of advanced analytical techniques to chemical substances", Tokyo Metropolitan University
- 2007: Ambleside, England - Co-organiser and Session Chair 7th CCPN Meeting - NMR of problematic biological systems
- 2006: Ambleside, England - Co-organiser and Session Chair 6th CCPN Meeting - Effective and Rapid Structure Determination by NMR
- 2005: Ambleside, England - Co-organiser and Session Chair 5th CCPN Meeting - NMR and Molecular Interaction
- 1999 - 2003: MRC Career Development Fellowship