Imperial College London

ProfessorThomasMeier

Faculty of Natural SciencesDepartment of Life Sciences

Chair in Structural Biology
 
 
 
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Contact

 

+44 (0)20 7594 3056t.meier Website

 
 
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Location

 

501Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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36 results found

Blum TB, Hahn A, Meier T, Davies KM, Kuhlbrandt Wet al., 2019, Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows, Proceedings of the National Academy of Sciences of the United States of America, Vol: 116, Pages: 4250-4255, ISSN: 0027-8424

Mitochondrial ATP synthases form dimers, which assemble intolong ribbons at the rims of the inner membrane cristae. We re-constituted detergent-purified mitochondrial ATP synthase dimersfrom the green algaPolytomellasp. and the yeastYarrowialipolyticainto liposomes and examined them by electron cryo-tomography. Tomographic volumes revealed that ATP synthasedimers from both species self-assemble into rows and bend thelipid bilayer locally. The dimer rows and the induced degree ofmembrane curvature closely resemble those in the inner mem-brane cristae. Monomers of mitochondrial ATP synthase reconsti-tuted into liposomes do not bend membrane visibly and do notform rows. No specific lipids or proteins other than ATP synthasedimers are required for row formation and membrane remodelling.Long rows of ATP synthase dimers are a conserved feature ofmitochondrial inner membranes. They are required for cristaeformation and a main factor in mitochondrial morphogenesis.

Journal article

Barringer R, Illuminating the secrets of crystals: microcrystal electron diffraction in structural biology, Bioscience Horizons, ISSN: 1754-7431

X-ray crystallography (XRC) has visualised biological macromolecules in exquisite detail for over 50 years, relying on a combination of mathematical principles to offer insight into atomic structures. Crystals can diffract various elec-tromagnetic waves aside from the conventional X-ray, offering an alternative approach to crystallographic structural analysis. Microcrystal Electron Diffraction (MicroED) illuminates crystals with electron waves instead of X-rays. Two specialised groups have demonstrated that MicroED can give high resolution (often atomic) data, and now appears to be developing into a powerful alternative method to XRC or electron microscopy of macromolecules. How Mi-croED compares to XRC will be key to assessing it as a stand-alone crystallographic technique. This review presents a critical analysis of MicroED, with comments on theoretical and practical aspects and suggestions of further work and development.

Journal article

Hahn A, Vonck J, Mills D, Meier TK, Kühlbrandt Wet al., 2018, Structure, mechanism, and regulation of the chloroplast ATP synthase, Science, Vol: 360, ISSN: 0036-8075

INTRODUCTION:Green plant chloroplasts convert light into chemical energy, and adenosine triphosphate (ATP) generated by photosynthesis is the prime source of biologically useful energy on the planet. Plants produce ATP by the chloroplast F1Fo ATP synthase (cF1Fo), a macromolecular machine par excellence, driven by the electrochemical proton gradient across the photosynthetic membrane. It consists of 26 protein subunits, 17 of them wholly or partly membrane-embedded. ATP synthesis in the hydrophilic α3β3 head (cF1) is powered by the cFo rotary motor in the membrane. cFo contains a rotor ring of 14 c subunits, each with a conserved protonatable glutamate. Subunit a conducts the protons to and from the c-ring protonation sites. The central stalk of subunits γ and ε transmits the torque from the Fo motor to the catalytic cF1 head, resulting in the synthesis of three ATP per revolution. The peripheral stalk subunits b, b′, and δ act as a stator to prevent unproductive rotation of cF1 with cFo.All rotary ATP synthases are, in principle, fully reversible. To prevent wasteful ATP hydrolysis, cF1Fo has a redox switch that inhibits adenosine triphosphatase (ATPase) activity in the dark.RATIONALE:Understanding the molecular mechanisms of this elaborate nanomachine requires detailed structures of the whole complex, ideally at atomic resolution. Because of the dynamic nature of this membrane protein complex, crystallization has been difficult and no high-resolution structure of an entire, functional ATP synthase is available. We reconstituted cF1Fo from spinach chloroplasts into lipid nanodiscs and determined its structure by cryo–electron microscopy (cryo-EM). Cryo-EM is the ideal technique for this study because it can deliver high-resolution structures of large, dynamic macromolecular assemblies that adopt a mixture of conformational states.RESULTS:We present the cryo-EM structure of the intact cF1Fo ATP synthase in lipid nanodiscs a

Journal article

Dautant A, Meier TK, Hahn A, Tribouillard-Tanvier D, di Rago J-P, Kucharczyk Ret al., 2018, ATP synthase diseases of mitochondrial genetic origin, Frontiers in Physiology, Vol: 9, ISSN: 1664-042X

Devastating human neuromuscular disorders have been associated to defects in the ATP synthase. This enzyme is found in the inner mitochondrial membrane and catalyzes the last step in oxidative phosphorylation, which provides aerobic eukaryotes with ATP. With the advent of structures of complete ATP synthases, and the availability of genetically approachable systems such as the yeast Saccharomyces cerevisiae, we can begin to understand these molecular machines and their associated defects at the molecular level. In this review, we describe what is known about the clinical syndromes induced by 58 different mutations found in the mitochondrial genes encoding membrane subunits 8 and a of ATP synthase, and evaluate their functional consequences with respect to recently described cryo-EM structures.

Journal article

Eisel B, Hartrampf F, Meier TK, Trauner Det al., 2018, Reversible optical control of F1Fo-ATP synthase using photoswitchable inhibitors, FEBS Letters, Vol: 592, Pages: 343-355, ISSN: 0014-5793

F1Fo-ATP synthase is one of the best studied macromolecular machines in nature. It can be inhibited by a range of small molecules, which include the polyphenols resveratrol and piceatannol. Here, we introduce Photoswitchable Inhibitors of ATP Synthase, termed PIAS, which were synthetically derived from these polyphenols. They can be used to reversibly control the enzymatic activity of purified yeast Yarrowia lipolytica ATP synthase by light. Our experiments indicate that the PIAS described here bind to the same site in the ATP synthase F1 complex as the polyphenols in their trans form but they do not bind in their cis form. The new PIAS compounds could be useful tools for the optical precision control of ATP synthase in a variety of biochemical and biotechnological applications.

Journal article

Schulz S, Wilkes M, Mills DJ, Kühlbrandt W, Meier TKet al., 2017, Molecular architecture of the N type ATPase rotor ring from Burkholderia pseudomallei, Embo Reports, Vol: 18, Pages: 526-535, ISSN: 1469-3178

The genome of the highly infectious bacterium Burkholderia pseudomallei harbours an atp-operon that encodes an N-type rotary ATPase, in addition to an operon for a regular F-type rotary ATPase. The molecular architecture of N-type ATPases is unknown and their biochemical properties and cellular functions are largely unexplored. We studied the B. pseudomallei N1No-type ATPase and investigated the structure and ion specificity of its membrane-embedded c-ring rotor by single-particle electron cryo-microscopy. Of several amphiphilic compounds tested for solubilizing the complex, the choice of the low-density, low-CMC detergent LDAO was optimal in terms of map quality and resolution. The cryoEM map of the c-ring at 6.1 Å resolution reveals a heptadecameric oligomer with a molecular mass of ~141 kDa. Biochemical measurements indicate that the c17 ring is H+ specific, demonstrating that the ATPase is proton-coupled. The c17 ring stoichiometry results in a very high ion-to-ATP ratio of 5.7. We propose that this N-ATPase is a highly efficient proton pump that helps these melioidosis-causing bacteria to survive in the hostile, acidic environment of phagosomes.

Journal article

He CH, Preiss LP, Wang BW, Fu LF, Wen HW, Zhang XZ, Cui HC, Meier TK, Yin DYet al., 2016, Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds, Chemmedchem, Vol: 12, Pages: 106-119, ISSN: 1860-7187

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets.

Journal article

Hahn A, Parey K, Bublitz M, Mills DJ, Zickermann V, Vonck J, Kühlbrandt W, Meier Tet al., 2016, Structure of a Complete ATP Synthase Dimer Reveals the Molecular Basis of Inner Mitochondrial Membrane Morphology, Molecular Cell, Vol: 63, Pages: 1-12, ISSN: 1097-4164

We determined the structure of a complete, dimeric F1Fo-ATP synthase from yeast Yarrowia lipolytica mitochondria by a combination of cryo-EM and X-ray crystallography. The final structure resolves 58 of the 60 dimer subunits. Horizontal helices of subunit a in Fo wrap around the c-ring rotor, and a total of six vertical helices assigned to subunits a, b, f, i, and 8 span the membrane. Subunit 8 (A6L in human) is an evolutionary derivative of the bacterial b subunit. On the lumenal membrane surface, subunit f establishes direct contact between the two monomers. Comparison with a cryo-EM map of the F1Fo monomer identifies subunits e and g at the lateral dimer interface. They do not form dimer contacts but enable dimer formation by inducing a strong membrane curvature of ∼100°. Our structure explains the structural basis of cristae formation in mitochondria, a landmark signature of eukaryotic cell morphology.

Journal article

Preiss L, Eisel B, Grell E, Eckhardt-Strelau L, Yildiz O, Koul A, Meier TKet al., 2016, Structural characterization of the mycobacterial ATP synthase c-ring and its interaction with the novel anti-tuberculosis drug Bedaquiline, Publisher: INT UNION CRYSTALLOGRAPHY, Pages: S210-S210, ISSN: 2053-2733

Conference paper

Preiss L, Hicks DB, Suzuki S, Meier T, Krulwich TAet al., 2015, Alkaliphilic bacteria with impact on industrial applications, concepts of early life forms, and bioenergetics of ATP synthesis, Frontiers in Bioengineering and Biotechnology, Vol: 3, ISSN: 2296-4185

Alkaliphilic bacteria typically grow well at pH 9, with the most extremophilic strains growing up to pH values as high as pH 12–13. Interest in extreme alkaliphiles arises because they are sources of useful, stable enzymes, and the cells themselves can be used for biotechnological and other applications at high pH. In addition, alkaline hydrothermal vents represent an early evolutionary niche for alkaliphiles and novel extreme alkaliphiles have also recently been found in alkaline serpentinizing sites. A third focus of interest in alkaliphiles is the challenge raised by the use of proton-coupled ATP synthases for oxidative phosphorylation by non-fermentative alkaliphiles. This creates a problem with respect to tenets of the chemiosmotic model that remains the core model for the bioenergetics of oxidative phosphorylation. Each of these facets of alkaliphilic bacteria will be discussed with a focus on extremely alkaliphilic Bacillus strains. These alkaliphilic bacteria have provided a cogent experimental system to probe adaptations that enable their growth and oxidative phosphorylation at high pH. Adaptations are clearly needed to enable secreted or partially exposed enzymes or protein complexes to function at the high external pH. Also, alkaliphiles must maintain a cytoplasmic pH that is significantly lower than the pH of the outside medium. This protects cytoplasmic components from an external pH that is alkaline enough to impair their stability or function. However, the pH gradient across the cytoplasmic membrane, with its orientation of more acidic inside than outside, is in the reverse of the productive orientation for bioenergetic work. The reversed gradient reduces the trans-membrane proton-motive force available to energize ATP synthesis. Multiple strategies are hypothesized to be involved in enabling alkaliphiles to circumvent the challenge of a low bulk proton-motive force energizing proton-coupled ATP synthesis at high pH.

Journal article

Preiss L, Langer JD, Yildiz O, Eckhardt-Strelau L, Guillemont JEG, Koul A, Meier Tet al., 2015, Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline., Science Advances, Vol: 1, Pages: e1500106-e1500106, ISSN: 2375-2548

Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring’s ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.

Journal article

Leone V, Pogoryelov D, Meier T, Faraldo-Gómez JDet al., 2015, On the principle of ion selectivity in Na+/H+-coupled membrane proteins: Experimental and theoretical studies of an ATP synthase rotor, Proceedings of the National Academy of Sciences, Vol: 112, Pages: E1057-E1066, ISSN: 0027-8424

Journal article

Matthies D, Zhou W, Klyszejko AL, Anselmi C, Yildiz Ö, Brandt K, Müller V, Faraldo-Gómez JD, Meier Tet al., 2014, High-resolution structure and mechanism of an F/V-hybrid rotor ring in a Na+-coupled ATP synthase, Nature Communications, Vol: 5

Journal article

Preiss L, Langer JD, Hicks DB, Liu J, Yildiz Ö, Krulwich TA, Meier Tet al., 2014, The c-ring ion binding site of the ATP synthase fromBacillus pseudofirmus OF4 is adapted to alkaliphilic lifestyle, Molecular Microbiology, Vol: 92, Pages: 973-984, ISSN: 0950-382X

Journal article

Leone V, Pogoryelov D, Meier T, Grell E, Faraldo-Gómez JDet al., 2014, Experimental Determination of the Ion Selectivity of an ATP-Synthase Membrane Rotor by Isothermal Titration Calorimetry, Biophysical Journal, Vol: 106, Pages: 372a-372a, ISSN: 0006-3495

Journal article

Schulz S, Iglesias-Cans M, Krah A, Yildiz Ö, Leone V, Matthies D, Cook GM, Faraldo-Gómez JD, Meier Tet al., 2013, A New Type of Na+-Driven ATP Synthase Membrane Rotor with a Two-Carboxylate Ion-Coupling Motif, PLOS Biology, Vol: 11, ISSN: 1545-7885

The anaerobic bacterium Fusobacterium nucleatum uses glutamate decarboxylation to generate a transmembrane gradient of Na+. Here, we demonstrate that this ion-motive force is directly coupled to ATP synthesis, via an F1Fo-ATP synthase with a novel Na+ recognition motif, shared by other human pathogens. Molecular modeling and free-energy simulations of the rotary element of the enzyme, the c-ring, indicate Na+ specificity in physiological settings. Consistently, activity measurements showed Na+ stimulation of the enzyme, either membrane-embedded or isolated, and ATP synthesis was sensitive to the Na+ ionophore monensin. Furthermore, Na+ has a protective effect against inhibitors targeting the ion-binding sites, both in the complete ATP synthase and the isolated c-ring. Definitive evidence of Na+ coupling is provided by two identical crystal structures of the c11 ring, solved by X-ray crystallography at 2.2 and 2.6 Å resolution, at pH 5.3 and 8.7, respectively. Na+ ions occupy all binding sites, each coordinated by four amino acids and a water molecule. Intriguingly, two carboxylates instead of one mediate ion binding. Simulations and experiments demonstrate that this motif implies that a proton is concurrently bound to all sites, although Na+ alone drives the rotary mechanism. The structure thus reveals a new mode of ion coupling in ATP synthases and provides a basis for drug-design efforts against this opportunistic pathogen.

Journal article

Preiss L, Klyszejko AL, Hicks DB, Liu J, Fackelmayer OJ, Yildiz O, Krulwich TA, Meier Tet al., 2013, The c-ring stoichiometry of ATP synthase is adapted to cell physiological requirements of alkaliphilic Bacillus pseudofirmus OF4, Proceedings of the National Academy of Sciences, Vol: 110, Pages: 7874-7879, ISSN: 0027-8424

Journal article

Preiss L, Eckhardt-Strelau L, Langer J, Koul A, Meier Tet al., 2012, A novel TB drug targets the ATP synthase rotor ring of mycobacteria, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol: 1817, Pages: S22-S22, ISSN: 0005-2728

Journal article

Pogoryelov D, Klyszejko AL, Krasnoselska GO, Heller E-M, Leone V, Langer JD, Vonck J, Muller DJ, Faraldo-Gómez JD, Meier Tet al., 2012, Engineering rotor ring stoichiometries in the ATP synthase, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol: 1817, Pages: S21-S21, ISSN: 0005-2728

Journal article

Krasnoselska GO, Pogoryelov D, Krah A, Langer JD, Faraldo-Gómez JD, Meier Tet al., 2012, Tuning the ion specificity of the ATP synthase rotor, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol: 1817, Pages: S17-S17, ISSN: 0005-2728

Journal article

Hakulinen JK, Klyszejko AL, Hoffmann J, Eckhardt-Strelau L, Brutschy B, Vonck J, Meier Tet al., 2012, Structural study on the architecture of the bacterial ATP synthase Fomotor, Proceedings of the National Academy of Sciences, Vol: 109, Pages: E2050-E2056, ISSN: 0027-8424

Journal article

Pogoryelov D, Klyszejko AL, Krasnoselska GO, Heller E-M, Leone V, Langer JD, Vonck J, Muller DJ, Faraldo-Gomez JD, Meier Tet al., 2012, Engineering rotor ring stoichiometries in the ATP synthase, Proceedings of the National Academy of Sciences, Vol: 109, Pages: E1599-E1608, ISSN: 0027-8424

Journal article

Symersky J, Pagadala V, Osowski D, Krah A, Meier T, Faraldo-Gómez JD, Mueller DMet al., 2012, Structure of the c10 ring of the yeast mitochondrial ATP synthase in the open conformation, Nature Structural & Molecular Biology, Vol: 19, Pages: 485-491, ISSN: 1545-9993

Journal article

Matthies D, Haberstock S, Joos F, Dötsch V, Vonck J, Bernhard F, Meier Tet al., 2011, Cell-Free Expression and Assembly of ATP Synthase, Journal of Molecular Biology, Vol: 413, Pages: 593-603, ISSN: 0022-2836

Journal article

Pogoryelov D, Krah A, Langer JD, Yildiz Ö, Faraldo-Gómez JD, Meier Tet al., 2010, Microscopic rotary mechanism of ion translocation in the Fo complex of ATP synthases, Nature Chemical Biology, Vol: 6, Pages: 891-899, ISSN: 1552-4450

Journal article

Preiss L, Yildiz Ö, Hicks DB, Krulwich TA, Meier Tet al., 2010, A New Type of Proton Coordination in an F1Fo-ATP Synthase Rotor Ring, PLoS Biology, Vol: 8, Pages: e1000443-e1000443

Journal article

Krah A, Pogoryelov D, Langer J, Bond PJ, Meier T, Faraldo-Gómez JDet al., 2010, Structural basis for the ion selectivity of F-ATP-synthase c-ring rotors, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol: 1797, Pages: 35-35, ISSN: 0005-2728

Journal article

Pogoryelov D, Yildiz Ö, Faraldo-Gómez JD, Meier Tet al., 2009, High-resolution structure of the rotor ring of a proton-dependent ATP synthase, Nature Structural & Molecular Biology, Vol: 16, Pages: 1068-1073, ISSN: 1545-9993

Journal article

Meier T, Krah A, Bond PJ, Pogoryelov D, Diederichs K, Faraldo-Gómez JDet al., 2009, Complete Ion-Coordination Structure in the Rotor Ring of Na+-Dependent F-ATP Synthases, Journal of Molecular Biology, Vol: 391, Pages: 498-507, ISSN: 0022-2836

Journal article

Pogoryelov D, Schlattner U, Meier T, Dimroth Pet al., 2008, S1.35 The rotor subunit interface of the ATP synthase from Ilyobacter tartaricus, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol: 1777, Pages: S17-S17, ISSN: 0005-2728

Journal article

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