[{"publisher":"Springer Nature","department":[{"_id":"LeSa"}],"publication_status":"published","pmid":1,"year":"2020","acknowledgement":"This work was funded by the Medical Research Council, UK and IST Austria. We thank the European Synchrotron Radiation Facility and the Diamond Light Source for provision of synchrotron radiation facilities. We are grateful to the staff of beamlines ID29, ID23-2 (ESRF, Grenoble, France) and I03 (Diamond Light Source, Didcot, UK) for assistance. Data processing was performed at the IST high-performance computing cluster.","volume":11,"date_updated":"2023-08-22T09:03:00Z","date_created":"2020-08-30T22:01:10Z","related_material":{"link":[{"description":"News on IST Homepage","relation":"press_release","url":"https://ist.ac.at/en/news/mystery-of-giant-proton-pump-solved/"}]},"author":[{"last_name":"Gutierrez-Fernandez","first_name":"Javier","id":"3D9511BA-F248-11E8-B48F-1D18A9856A87","full_name":"Gutierrez-Fernandez, Javier"},{"first_name":"Karol","last_name":"Kaszuba","id":"3FDF9472-F248-11E8-B48F-1D18A9856A87","full_name":"Kaszuba, Karol"},{"full_name":"Minhas, Gurdeep S.","last_name":"Minhas","first_name":"Gurdeep S."},{"last_name":"Baradaran","first_name":"Rozbeh","full_name":"Baradaran, Rozbeh"},{"id":"4187dfe4-ec23-11ea-ae46-f08ab378313a","first_name":"Margherita","last_name":"Tambalo","full_name":"Tambalo, Margherita"},{"first_name":"David T.","last_name":"Gallagher","full_name":"Gallagher, David T."},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-0977-7989","first_name":"Leonid A","last_name":"Sazanov","full_name":"Sazanov, Leonid A"}],"article_number":"4135","file_date_updated":"2020-08-31T13:40:00Z","quality_controlled":"1","isi":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"external_id":{"isi":["000607072900001"],"pmid":["32811817"]},"oa":1,"language":[{"iso":"eng"}],"doi":"10.1038/s41467-020-17957-0","publication_identifier":{"eissn":["20411723"]},"month":"08","intvolume":" 11","title":"Key role of quinone in the mechanism of respiratory complex I","ddc":["570"],"status":"public","_id":"8318","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","oa_version":"Published Version","file":[{"relation":"main_file","file_id":"8326","checksum":"52b96f41d7d0db9728064c08da00d030","success":1,"date_created":"2020-08-31T13:40:00Z","date_updated":"2020-08-31T13:40:00Z","access_level":"open_access","file_name":"2020_NatComm_Gutierrez-Fernandez.pdf","file_size":7527373,"content_type":"application/pdf","creator":"cziletti"}],"type":"journal_article","issue":"1","abstract":[{"lang":"eng","text":"Complex I is the first and the largest enzyme of respiratory chains in bacteria and mitochondria. The mechanism which couples spatially separated transfer of electrons to proton translocation in complex I is not known. Here we report five crystal structures of T. thermophilus enzyme in complex with NADH or quinone-like compounds. We also determined cryo-EM structures of major and minor native states of the complex, differing in the position of the peripheral arm. Crystal structures show that binding of quinone-like compounds (but not of NADH) leads to a related global conformational change, accompanied by local re-arrangements propagating from the quinone site to the nearest proton channel. Normal mode and molecular dynamics analyses indicate that these are likely to represent the first steps in the proton translocation mechanism. Our results suggest that quinone binding and chemistry play a key role in the coupling mechanism of complex I."}],"article_type":"original","citation":{"short":"J. Gutierrez-Fernandez, K. Kaszuba, G.S. Minhas, R. Baradaran, M. Tambalo, D.T. Gallagher, L.A. Sazanov, Nature Communications 11 (2020).","mla":"Gutierrez-Fernandez, Javier, et al. “Key Role of Quinone in the Mechanism of Respiratory Complex I.” Nature Communications, vol. 11, no. 1, 4135, Springer Nature, 2020, doi:10.1038/s41467-020-17957-0.","chicago":"Gutierrez-Fernandez, Javier, Karol Kaszuba, Gurdeep S. Minhas, Rozbeh Baradaran, Margherita Tambalo, David T. Gallagher, and Leonid A Sazanov. “Key Role of Quinone in the Mechanism of Respiratory Complex I.” Nature Communications. Springer Nature, 2020. https://doi.org/10.1038/s41467-020-17957-0.","ama":"Gutierrez-Fernandez J, Kaszuba K, Minhas GS, et al. Key role of quinone in the mechanism of respiratory complex I. Nature Communications. 2020;11(1). doi:10.1038/s41467-020-17957-0","apa":"Gutierrez-Fernandez, J., Kaszuba, K., Minhas, G. S., Baradaran, R., Tambalo, M., Gallagher, D. T., & Sazanov, L. A. (2020). Key role of quinone in the mechanism of respiratory complex I. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-020-17957-0","ieee":"J. Gutierrez-Fernandez et al., “Key role of quinone in the mechanism of respiratory complex I,” Nature Communications, vol. 11, no. 1. Springer Nature, 2020.","ista":"Gutierrez-Fernandez J, Kaszuba K, Minhas GS, Baradaran R, Tambalo M, Gallagher DT, Sazanov LA. 2020. Key role of quinone in the mechanism of respiratory complex I. Nature Communications. 11(1), 4135."},"publication":"Nature Communications","date_published":"2020-08-18T00:00:00Z","scopus_import":"1","has_accepted_license":"1","article_processing_charge":"No","day":"18"},{"publist_id":"6108","ec_funded":1,"publisher":"Nature Publishing Group","department":[{"_id":"LeSa"}],"publication_status":"published","pmid":1,"year":"2016","volume":538,"date_created":"2018-12-11T11:50:49Z","date_updated":"2021-01-12T06:49:13Z","author":[{"id":"5BFF67CE-02D1-11E9-B11A-A5A4D7DFFFD0","first_name":"Karol","last_name":"Fiedorczuk","full_name":"Fiedorczuk, Karol"},{"full_name":"Letts, James A","first_name":"James A","last_name":"Letts","id":"322DA418-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-9864-3586"},{"full_name":"Degliesposti, Gianluca","last_name":"Degliesposti","first_name":"Gianluca"},{"id":"3FDF9472-F248-11E8-B48F-1D18A9856A87","last_name":"Kaszuba","first_name":"Karol","full_name":"Kaszuba, Karol"},{"full_name":"Skehel, Mark","last_name":"Skehel","first_name":"Mark"},{"last_name":"Sazanov","first_name":"Leonid A","orcid":"0000-0002-0977-7989","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","full_name":"Sazanov, Leonid A"}],"month":"10","project":[{"name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes (FEBS)","_id":"2593EBD6-B435-11E9-9278-68D0E5697425"},{"_id":"2590DB08-B435-11E9-9278-68D0E5697425","grant_number":"701309","name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes (H2020)","call_identifier":"H2020"}],"quality_controlled":"1","external_id":{"pmid":["27595392"]},"main_file_link":[{"open_access":"1","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164932/"}],"oa":1,"language":[{"iso":"eng"}],"doi":"10.1038/nature19794","type":"journal_article","issue":"7625","abstract":[{"text":"Mitochondrial complex I (also known as NADH:ubiquinone oxidoreductase) contributes to cellular energy production by transferring electrons from NADH to ubiquinone coupled to proton translocation across the membrane. It is the largest protein assembly of the respiratory chain with a total mass of 970 kilodaltons. Here we present a nearly complete atomic structure of ovine (Ovis aries) mitochondrial complex I at 3.9 Å resolution, solved by cryo-electron microscopy with cross-linking and mass-spectrometry mapping experiments. All 14 conserved core subunits and 31 mitochondria-specific supernumerary subunits are resolved within the L-shaped molecule. The hydrophilic matrix arm comprises flavin mononucleotide and 8 iron-sulfur clusters involved in electron transfer, and the membrane arm contains 78 transmembrane helices, mostly contributed by antiporter-like subunits involved in proton translocation. Supernumerary subunits form an interlinked, stabilizing shell around the conserved core. Tightly bound lipids (including cardiolipins) further stabilize interactions between the hydrophobic subunits. Subunits with possible regulatory roles contain additional cofactors, NADPH and two phosphopantetheine molecules, which are shown to be involved in inter-subunit interactions. We observe two different conformations of the complex, which may be related to the conformationally driven coupling mechanism and to the active-deactive transition of the enzyme. Our structure provides insight into the mechanism, assembly, maturation and dysfunction of mitochondrial complex I, and allows detailed molecular analysis of disease-causing mutations.","lang":"eng"}],"intvolume":" 538","status":"public","title":"Atomic structure of the entire mammalian mitochondrial complex i","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","_id":"1226","oa_version":"Submitted Version","scopus_import":1,"article_processing_charge":"No","day":"20","page":"406 - 410","article_type":"original","citation":{"chicago":"Fiedorczuk, Karol, James A Letts, Gianluca Degliesposti, Karol Kaszuba, Mark Skehel, and Leonid A Sazanov. “Atomic Structure of the Entire Mammalian Mitochondrial Complex I.” Nature. Nature Publishing Group, 2016. https://doi.org/10.1038/nature19794.","short":"K. Fiedorczuk, J.A. Letts, G. Degliesposti, K. Kaszuba, M. Skehel, L.A. Sazanov, Nature 538 (2016) 406–410.","mla":"Fiedorczuk, Karol, et al. “Atomic Structure of the Entire Mammalian Mitochondrial Complex I.” Nature, vol. 538, no. 7625, Nature Publishing Group, 2016, pp. 406–10, doi:10.1038/nature19794.","apa":"Fiedorczuk, K., Letts, J. A., Degliesposti, G., Kaszuba, K., Skehel, M., & Sazanov, L. A. (2016). Atomic structure of the entire mammalian mitochondrial complex i. Nature. Nature Publishing Group. https://doi.org/10.1038/nature19794","ieee":"K. Fiedorczuk, J. A. Letts, G. Degliesposti, K. Kaszuba, M. Skehel, and L. A. Sazanov, “Atomic structure of the entire mammalian mitochondrial complex i,” Nature, vol. 538, no. 7625. Nature Publishing Group, pp. 406–410, 2016.","ista":"Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M, Sazanov LA. 2016. Atomic structure of the entire mammalian mitochondrial complex i. Nature. 538(7625), 406–410.","ama":"Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M, Sazanov LA. Atomic structure of the entire mammalian mitochondrial complex i. Nature. 2016;538(7625):406-410. doi:10.1038/nature19794"},"publication":"Nature","date_published":"2016-10-20T00:00:00Z"},{"citation":{"chicago":"Postila, Pekka, Karol Kaszuba, Patryk Kuleta, Ilpo Vattulainen, Marcin Sarewicz, Artur Osyczka, and Tomasz Róg. “Atomistic Determinants of Co-Enzyme Q Reduction at the Qi-Site of the Cytochrome Bc1 Complex.” Scientific Reports. Nature Publishing Group, 2016. https://doi.org/10.1038/srep33607.","short":"P. Postila, K. Kaszuba, P. Kuleta, I. Vattulainen, M. Sarewicz, A. Osyczka, T. Róg, Scientific Reports 6 (2016).","mla":"Postila, Pekka, et al. “Atomistic Determinants of Co-Enzyme Q Reduction at the Qi-Site of the Cytochrome Bc1 Complex.” Scientific Reports, vol. 6, 33607, Nature Publishing Group, 2016, doi:10.1038/srep33607.","ieee":"P. Postila et al., “Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex,” Scientific Reports, vol. 6. Nature Publishing Group, 2016.","apa":"Postila, P., Kaszuba, K., Kuleta, P., Vattulainen, I., Sarewicz, M., Osyczka, A., & Róg, T. (2016). Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex. Scientific Reports. Nature Publishing Group. https://doi.org/10.1038/srep33607","ista":"Postila P, Kaszuba K, Kuleta P, Vattulainen I, Sarewicz M, Osyczka A, Róg T. 2016. Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex. Scientific Reports. 6, 33607.","ama":"Postila P, Kaszuba K, Kuleta P, et al. Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex. Scientific Reports. 2016;6. doi:10.1038/srep33607"},"publication":"Scientific Reports","date_published":"2016-09-26T00:00:00Z","scopus_import":1,"has_accepted_license":"1","day":"26","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","_id":"1276","intvolume":" 6","status":"public","title":"Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex","ddc":["576"],"pubrep_id":"691","file":[{"file_id":"5261","relation":"main_file","checksum":"07c591c1250ebef266333cbc3228b4dd","date_created":"2018-12-12T10:17:09Z","date_updated":"2020-07-14T12:44:42Z","access_level":"open_access","file_name":"IST-2016-691-v1+1_srep33607.pdf","creator":"system","file_size":1960563,"content_type":"application/pdf"}],"oa_version":"Published Version","type":"journal_article","abstract":[{"lang":"eng","text":"The cytochrome (cyt) bc 1 complex is an integral component of the respiratory electron transfer chain sustaining the energy needs of organisms ranging from humans to bacteria. Due to its ubiquitous role in the energy metabolism, both the oxidation and reduction of the enzyme's substrate co-enzyme Q has been studied vigorously. Here, this vast amount of data is reassessed after probing the substrate reduction steps at the Q i-site of the cyt bc 1 complex of Rhodobacter capsulatus using atomistic molecular dynamics simulations. The simulations suggest that the Lys251 side chain could rotate into the Q i-site to facilitate binding of half-protonated semiquinone-a reaction intermediate that is potentially formed during substrate reduction. At this bent pose, the Lys251 forms a salt bridge with the Asp252, thus making direct proton transfer possible. In the neutral state, the lysine side chain stays close to the conserved binding location of cardiolipin (CL). This back-and-forth motion between the CL and Asp252 indicates that Lys251 functions as a proton shuttle controlled by pH-dependent negative feedback. The CL/K/D switching, which represents a refinement to the previously described CL/K pathway, fine-tunes the proton transfer process. Lastly, the simulation data was used to formulate a mechanism for reducing the substrate at the Q i-site."}],"oa":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"quality_controlled":"1","doi":"10.1038/srep33607","language":[{"iso":"eng"}],"month":"09","acknowledgement":"We wish to thank CSC – IT Centre for Science (Espoo, Finland) for computational resources. For financial support, we wish to thank the Academy of Finland (TR, IV and PAP; Center of Excellence in Biomembrane Research (IV, TR)), the Finnish Doctoral Programme in Computational Sciences (KK), the Sigrid Juselius Foundation (IV), the Paulo Foundation (PAP), and the European Research Council (IV, TR; Advanced Grant project CROWDED-PRO-LIPIDS). AO acknowledges The Wellcome Trust International Senior Research Fellowship.","year":"2016","publisher":"Nature Publishing Group","department":[{"_id":"LeSa"}],"publication_status":"published","author":[{"last_name":"Postila","first_name":"Pekka","full_name":"Postila, Pekka"},{"id":"3FDF9472-F248-11E8-B48F-1D18A9856A87","first_name":"Karol","last_name":"Kaszuba","full_name":"Kaszuba, Karol"},{"first_name":"Patryk","last_name":"Kuleta","full_name":"Kuleta, Patryk"},{"full_name":"Vattulainen, Ilpo","last_name":"Vattulainen","first_name":"Ilpo"},{"full_name":"Sarewicz, Marcin","first_name":"Marcin","last_name":"Sarewicz"},{"full_name":"Osyczka, Artur","first_name":"Artur","last_name":"Osyczka"},{"full_name":"Róg, Tomasz","last_name":"Róg","first_name":"Tomasz"}],"volume":6,"date_created":"2018-12-11T11:51:05Z","date_updated":"2021-01-12T06:49:34Z","article_number":"33607","publist_id":"6040","file_date_updated":"2020-07-14T12:44:42Z"}]