Cargando…
Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I
Respiratory complex I, a key enzyme in mammalian metabolism, captures the energy released by reduction of ubiquinone by NADH to drive protons across the inner mitochondrial membrane, generating the proton-motive force for ATP synthesis. Despite remarkable advances in structural knowledge of this com...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396290/ https://www.ncbi.nlm.nih.gov/pubmed/37531432 http://dx.doi.org/10.1126/sciadv.adi1359 |
_version_ | 1785083727487959040 |
---|---|
author | Grba, Daniel N. Chung, Injae Bridges, Hannah R. Agip, Ahmed-Noor A. Hirst, Judy |
author_facet | Grba, Daniel N. Chung, Injae Bridges, Hannah R. Agip, Ahmed-Noor A. Hirst, Judy |
author_sort | Grba, Daniel N. |
collection | PubMed |
description | Respiratory complex I, a key enzyme in mammalian metabolism, captures the energy released by reduction of ubiquinone by NADH to drive protons across the inner mitochondrial membrane, generating the proton-motive force for ATP synthesis. Despite remarkable advances in structural knowledge of this complicated membrane-bound enzyme, its mechanism of catalysis remains controversial. In particular, how ubiquinone reduction is coupled to proton pumping and the pathways and mechanisms of proton translocation are contested. We present a 2.4-Å resolution cryo-EM structure of complex I from mouse heart mitochondria in the closed, active (ready-to-go) resting state, with 2945 water molecules modeled. By analyzing the networks of charged and polar residues and water molecules present, we evaluate candidate pathways for proton transfer through the enzyme, for the chemical protons for ubiquinone reduction, and for the protons transported across the membrane. Last, we compare our data to the predictions of extant mechanistic models, and identify key questions to answer in future work to test them. |
format | Online Article Text |
id | pubmed-10396290 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-103962902023-08-03 Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I Grba, Daniel N. Chung, Injae Bridges, Hannah R. Agip, Ahmed-Noor A. Hirst, Judy Sci Adv Biomedicine and Life Sciences Respiratory complex I, a key enzyme in mammalian metabolism, captures the energy released by reduction of ubiquinone by NADH to drive protons across the inner mitochondrial membrane, generating the proton-motive force for ATP synthesis. Despite remarkable advances in structural knowledge of this complicated membrane-bound enzyme, its mechanism of catalysis remains controversial. In particular, how ubiquinone reduction is coupled to proton pumping and the pathways and mechanisms of proton translocation are contested. We present a 2.4-Å resolution cryo-EM structure of complex I from mouse heart mitochondria in the closed, active (ready-to-go) resting state, with 2945 water molecules modeled. By analyzing the networks of charged and polar residues and water molecules present, we evaluate candidate pathways for proton transfer through the enzyme, for the chemical protons for ubiquinone reduction, and for the protons transported across the membrane. Last, we compare our data to the predictions of extant mechanistic models, and identify key questions to answer in future work to test them. American Association for the Advancement of Science 2023-08-02 /pmc/articles/PMC10396290/ /pubmed/37531432 http://dx.doi.org/10.1126/sciadv.adi1359 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Grba, Daniel N. Chung, Injae Bridges, Hannah R. Agip, Ahmed-Noor A. Hirst, Judy Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I |
title | Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I |
title_full | Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I |
title_fullStr | Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I |
title_full_unstemmed | Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I |
title_short | Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I |
title_sort | investigation of hydrated channels and proton pathways in a high-resolution cryo-em structure of mammalian complex i |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396290/ https://www.ncbi.nlm.nih.gov/pubmed/37531432 http://dx.doi.org/10.1126/sciadv.adi1359 |
work_keys_str_mv | AT grbadanieln investigationofhydratedchannelsandprotonpathwaysinahighresolutioncryoemstructureofmammaliancomplexi AT chunginjae investigationofhydratedchannelsandprotonpathwaysinahighresolutioncryoemstructureofmammaliancomplexi AT bridgeshannahr investigationofhydratedchannelsandprotonpathwaysinahighresolutioncryoemstructureofmammaliancomplexi AT agipahmednoora investigationofhydratedchannelsandprotonpathwaysinahighresolutioncryoemstructureofmammaliancomplexi AT hirstjudy investigationofhydratedchannelsandprotonpathwaysinahighresolutioncryoemstructureofmammaliancomplexi |