Frank Sobott

About

My research is aimed at development and applications of methods based on “native” mass spectrometry and ion mobility and associated structural proteomics and computational techniques, in order to understand and characterize noncovalent interactions in chemistry and biology. I am particularly motivated by understanding structure and dynamics of molecules and complexes of high biochemical and biomedical relevance, in order to provide innovative tools for the development of novel drugs. I am recognized as one of the key, early pioneers of "native MS" and achievements during my career over the last 25 years include: 1) Developed novel method for gentle ionization of supra- and biomolecular complexes which uses liquid jets/droplets in combination with a desorption laser ("LILBID", Anal. Chem., 69 (1997), 3587 and Angew. Chem. Int. Ed., 39 (2000), 3901) 2) First high-mass modified MS for large protein complexes and application to study intact ribosomes (Proc. Natl. Acad. Sci. USA, 102 (2005), 8192) 3) Significant contributions to 27 x-ray structures at Structural Genomics Consortium (PDB; Proc. Natl. Acad. Sci. USA, 103 (2006), 17237) 4) Utilized hydrophobically stabilized detergent micelles and native MS with ion mobility and molecular modelling to characterize conformational transitions of an ion channel (MscL), capturing intermediate opening states 5) Developed top-down protein fragmentation technique which links information on protein higher-order structure (conformation, assembly, ligand binding) with sequence data in one experiment - particularly useful for the characterization of disordered regions 6) Characterized conformational space, binding sites and effects of small molecules on a-synuclein folding and assembly, enabling conformation-sensitive screening of drug candidates even for non-specific binders which modulate amyloid aggregation and toxicity 7) Contributed to fundamental biophysical understanding of protein structural dynamics, determinants of intrinsic disorder and influence of charge on structure (J. Am. Chem. Soc., 137 (2015), 4236 and J. Am. Soc. Mass Spectrom., 28 (2017), 69) 8) Engaged in dissemination of structural proteomics know-how to students, structural biologists and colleagues in biopharma industry, thereby establishing best practice application of these tools to characterize proteins of therapeutic interest (Chair of COST Action, H2020 and Marie-Curie network subject to funding)

Work

University of Leeds
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Chair of Biomolecular Mass Spectrometry

United Kingdom of Great Britain and Northern Ireland

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Publications

Radical solutions: Principles and application of electron-based dissociation in mass spectrometry-based analysis of protein structure

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Mass Spectrometry Reviews

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The effect of reactive oxygen and nitrogen species on the structure of cytoglobin: A potential tumor suppressor

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Redox Biology

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A broader view on ion heating in traveling-wave devices using fragmentation of CsI clusters and extent of H˙ migration as molecular thermometers

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The Analyst

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A broader view on ion heating in traveling-wave devices using fragmentation of CsI clusters and extent of H migration as molecular thermometers

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Analyst

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A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover

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Nature Communications

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Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

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Journal of Chromatography A

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Antarctic fish versus human cytoglobins – The same but yet so different

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Journal of Inorganic Biochemistry

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Apparent activation energies of protein–protein complex dissociation in the gas–phase determined by electrospray mass spectrometry

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Analytical and Bioanalytical Chemistry

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AtaT blocks translation initiation by N-acetylation of the initiator tRNA<sup>fMet</sup>

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Nature Chemical Biology

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Conformational Space and Stability of ETD Charge Reduction Products of Ubiquitin

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Journal of the American Society for Mass Spectrometry

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Estimation of rates of reactions triggered by electron transfer in top-down mass spectrometry

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Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)

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Hidden States within Disordered Regions of the CcdA Antitoxin Protein

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Journal of the American Chemical Society

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Mechanisms of Peptide Oxidation by Hydroxyl Radicals: Insight at the Molecular Scale

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Journal of Physical Chemistry C

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Native mass spectrometry for the characterization of structure and interactions of membrane proteins

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Methods in Molecular Biology

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book

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics

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Molecular Cell

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Preprotein mature domains contain translocase targeting signals that are essential for secretion

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Journal of Cell Biology

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Proton Dynamics in Protein Mass Spectrometry

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Journal of Physical Chemistry Letters

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Raman optical activity of human α-synuclein in intrinsically disordered, micelle-bound α-helical, molten globule and oligomeric β-sheet state

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Journal of Raman Spectroscopy

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Specific sequences in the N-terminal domain of human small heat-shock protein HSPB6 dictate preferential hetero-oligomerization with the orthologue HSPB1

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Journal of Biological Chemistry

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The structural basis for dynamic DNA binding and bridging interactions which condense the bacterial centromere

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eLife

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ATP and autophosphorylation driven conformational changes of HipA kinase revealed by ion mobility and crosslinking mass spectrometry

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Analytical and Bioanalytical Chemistry

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Combining density functional theory (DFT) and collision cross-section (CCS) calculations to analyze the gas-phase behaviour of small molecules and their protonation site isomers

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Analyst

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Covalent adducts of melphalan with free amino acids and a model peptide studied by liquid chromatography/tandem mass spectrometry

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Rapid Communications in Mass Spectrometry

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Development of a novel antibody-tetrazine conjugate for bioorthogonal pretargeting

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Organic and Biomolecular Chemistry

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Gas-phase microsolvation of ubiquitin: Investigation of crown ether complexation sites using ion mobility-mass spectrometry

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Analyst

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Lipids modulate the conformational dynamics of a secondary multidrug transporter

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Nature Structural and Molecular Biology

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Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

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Analytical Chemistry

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The preferential heterodimerization of human small heat shock proteins HSPB1 and HSPB6 is dictated by the N-terminal domain

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Archives of Biochemistry and Biophysics

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Biophysical studies on interactions and assembly of full-size E3 ubiquitin ligase: Suppressor of cytokine signaling 2 (SOCS2)-elongin Bc-cullin 5-ring box protein 2 (RBX2)

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Journal of Biological Chemistry

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Bouncing off the walls: Excited protein complexes tell their story

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Chemistry and Biology

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Characterization of top-down ETD in a travelling-wave ion guide

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Methods

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Differences in the Elemental Isotope Definition May Lead to Errors in Modern Mass-Spectrometry-Based Proteomics

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Analytical Chemistry

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Electron transfer dissociation provides higher-order structural information of native and partially unfolded protein complexes

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Proteomics

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Extending native mass spectrometry approaches to integral membrane proteins

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Biological Chemistry

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Extensive charge reduction and dissociation of intact protein complexes following electron transfer on a quadrupole-ion mobility-time-of-flight MS

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Journal of the American Society for Mass Spectrometry

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Molecular basis for structural heterogeneity of an intrinsically disordered protein bound to a partner by combined ESI-IM-MS and modeling

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Journal of the American Society for Mass Spectrometry

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Protomers of benzocaine: Solvent and permittivity dependence

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Journal of the American Chemical Society

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Signal loss due to oligomerization in ELISA analysis of amyloid-beta can be recovered by a novel sample pre-treatment method

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MethodsX

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Specific and non-specific interactions of ParB with DNA: Implications for chromosome segregation

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Nucleic Acids Research

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Top-down mass spectrometry of intact membrane protein complexes reveals oligomeric state and sequence information in a single experiment

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Protein Science

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Understanding reaction pathways in top-down ETD by dissecting isotope distributions: A mammoth task

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International Journal of Mass Spectrometry

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ETD allows for native surface mapping of a 150 kDa noncovalent complex on a commercial Q-TWIMS-TOF instrument

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Journal of the American Society for Mass Spectrometry

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Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry

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Proceedings of the National Academy of Sciences of the United States of America

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The intrinsically disordered domain of the antitoxin phd chaperones the toxin doc against irreversible inactivation and misfolding

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Journal of Biological Chemistry

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Type III restriction endonucleases are heterotrimeric: Comprising one helicase-nuclease subunit and a dimeric methyltransferase that binds only one specific DNA

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Nucleic Acids Research

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Hfq binding changes the structure of Escherichia coli small noncoding RNAs OxyS and RprA, which are involved in the riboregulation of rpoS

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RNA

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LptA assembles into rod-like oligomers involving disorder-to-order transitions

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Journal of the American Society for Mass Spectrometry

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Native Mass Spectrometry Approaches Using Ion Mobility-Mass Spectrometry

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Analyzing Biomolecular Interactions by Mass Spectrometry

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book

Native ion mobility-mass spectrometry and related methods in structural biology

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Biochimica et Biophysica Acta - Proteins and Proteomics

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Organization of the BcgI restriction-modification protein for the cleavage of eight phosphodiester bonds in DNA

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Nucleic Acids Research

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Organization of the BcgI restriction-modification protein for the transfer of one methyl group to DNA

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Nucleic Acids Research

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Structural plasticity of histones H3-H4 facilitates their allosteric exchange between RbAp48 and ASF1

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Nature Structural and Molecular Biology

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Travelling wave ion mobility and negative ion fragmentation for the structural determination of N-linked glycans

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Electrophoresis

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Characterization of Vibrio cholerae Hfq provides novel insights into the role of the Hfq C-terminal region

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Journal of Molecular Biology

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Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia

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Journal of Neurology, Neurosurgery and Psychiatry

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The low-resolution solution structure of Vibrio cholerae Hfq in complex with Qrr1 sRNA

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Nucleic Acids Research

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Characterization of β2-microglobulin conformational intermediates associated to different fibrillation conditions

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Journal of Mass Spectrometry

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Compaction properties of an intrinsically disordered protein: Sic1 and its kinase-inhibitor domain

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Biophysical Journal

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Ion mobility mass spectrometry for extracting spectra of n-glycans directly from incubation mixtures following glycan release: Application to glycans from engineered glycoforms of intact, folded HIV gp120

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Journal of the American Society for Mass Spectrometry

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Metal and redox selectivity of protoporphyrin binding to the heme chaperone CcmE

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Metallomics

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Application of a proteolysis/mass spectrometry method for investigating the effects of inhibitors on hydroxylase structure

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Journal of Medicinal Chemistry

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Comparison of CID Versus ETD Based MS/MS Fragmentation for the Analysis of Protein Ubiquitination

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Journal of the American Society for Mass Spectrometry

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Quadrupole-time-of-flight mass spectrometer modified for higher-energy dissociation reduces protein assemblies to peptide fragments

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Analytical Chemistry

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Codon optimization can improve expression of human genes in Escherichia coli: A multi-gene study

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Protein Expression and Purification

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Structure of the Human Protein Kinase MPSK1 Reveals an Atypical Activation Loop Architecture

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Structure

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Structural and Functional Characterization of the Human Protein Kinase ASK1

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Structure

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The centaurin γ-1 GTPase-like domain functions as an NTPase

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Biochemical Journal

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Structural basis for protein-protein interactions in the 14-3-3 protein family

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Proceedings of the National Academy of Sciences of the United States of America

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Structure of an Hsp90-Cdc37-Cdk4 Complex

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Molecular Cell

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Tandem Mass Spectrometry Reveals the Quaternary Organization of Macromolecular Assemblies

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Chemistry and Biology

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The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins

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Journal of Molecular Biology

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Understanding Protein Interactions and Their Representation in the Gas Phase of the Mass Spectrometer

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Principles of Mass Spectrometry Applied to Biomolecules

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book

Heptameric (L12)<inf>6</inf>/L10 rather than canonical pentameric complexes are found by tandem MS of intact ribosomes from thermophilic bacteria

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Proceedings of the National Academy of Sciences of the United States of America

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The flight of macromolecular complexes in a mass spectrometer

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Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences

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Biochemical and structural studies of the interaction of Cdc37 with Hsp90

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Journal of Molecular Biology

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Characterising electrosprayed biomolecules using tandem-MS - The noncovalent GroEL chaperonin assembly

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International Journal of Mass Spectrometry

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Tandem Mass Spectrometry Defines the Stoichiometry and Quaternary Structural Arrangement of Tryptophan Molecules in the Multiprotein Complex TRAP

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Journal of the American Chemical Society

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Gas-phase dissociation pathways of a tetrameric protein complex

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International Journal of Mass Spectrometry

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Reactions of gold cluster cations Au<inf>n</inf><sup>+</sup> (n=1-12) with H<inf>2</inf>S and H<inf>2</inf>

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Journal of Chemical Physics

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Thermal dissociation of multimeric protein complexes by using nanoelectrospray mass spectrometry

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Analytical Chemistry

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A high-mass Q-TOF for the analysis of protein complexes

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Proceedings 50th ASMS Conference on Mass Spectrometry and Allied Topics

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conference-paper

A nano-electrospray investigation into the subunit exchange of small heat shock proteins

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Proceedings 50th ASMS Conference on Mass Spectrometry and Allied Topics

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conference-paper

A tandem mass spectrometer for improved transmission and analysis of large macromolecular assemblies

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Analytical Chemistry

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Protein complexes gain momentum

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Current Opinion in Structural Biology

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Subunit exchange of multimeric protein complexes: Real-time monitoring of subunit exchange between small heat shock proteins by using electrospray mass spectrometry

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Journal of Biological Chemistry

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Detection of intact hemoglobin from aqueous solution with laser desorption mass spectrometry

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Rapid Communications in Mass Spectrometry

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Speciation in solution: Silicate oligomers in aqueous solutions detected by mass spectrometry

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Angewandte Chemie - International Edition

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Studying noncovalent protein complexes in aqueous solution with laser desorption mass spectrometry

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International Journal of Mass Spectrometry

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Ionic clathrates from aqueous solutions detected with laser induced liquid beam ionization/desorption mass spectrometry

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International Journal of Mass Spectrometry

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Laser desorption mass spectrometry on liquid beams

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European Journal of Mass Spectrometry

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Examination of condensation products of Group 4 alkoxides with laser- induced liquid beam ionization/desorption mass spectrometry

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Chemistry - A European Journal

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Laser desorption mass spectrometry on thin liquid jets

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Fresenius' Journal of Analytical Chemistry

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Cation Selectivity of Natural and Synthetic lonophores Probed with Laser-Induced Liquid Beam Mass Spectrometry

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Analytical Chemistry

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