PMID- 28842531 OWN - NLM STAT- MEDLINE DCOM- 20180222 LR - 20181113 IS - 1470-8752 (Electronic) IS - 0300-5127 (Print) IS - 0300-5127 (Linking) VI - 45 IP - 5 DP - 2017 Oct 15 TI - Role of conformational change and K-path ligands in controlling cytochrome c oxidase activity. PG - 1087-1095 LID - 10.1042/BST20160138 [doi] AB - Given the central role of cytochrome c oxidase (CcO) in health and disease, it is an increasingly important question as to how the activity and efficiency of this key enzyme are regulated to respond to a variety of metabolic states. The present paper summarizes evidence for two modes of regulation of activity: first, by redox-induced conformational changes involving the K-proton uptake path; and secondly, by ligand binding to a conserved site immediately adjacent to the entrance of the K-path that leads to the active site. Both these phenomena highlight the importance of the K-path in control of CcO. The redox-induced structural changes are seen in both the two-subunit and a new four-subunit crystal structure of bacterial CcO and suggest a gating mechanism to control access of protons to the active site. A conserved ligand-binding site, first discovered as a bile salt/steroid site in bacterial and mammalian oxidases, is observed to bind an array of ligands, including nucleotides, detergents, and other amphipathic molecules. Highly variable effects on activity, seen for these ligands and mutations at the K-path entrance, can be explained by differing abilities to inhibit or stimulate K-path proton uptake by preventing or allowing water organization. A new mutant form in which the K-path is blocked by substituting the conserved carboxyl with a tryptophan clarifies the singularity of the K-path entrance site. Further study in eukaryotic systems will determine the physiological significance and pharmacological potential of ligand binding and conformational change in CcO. CI - (c) 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Liu, Jian AU - Liu J AD - Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd, East Lansing, MI 48824, U.S.A. FAU - Hiser, Carrie AU - Hiser C AD - Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd, East Lansing, MI 48824, U.S.A. FAU - Ferguson-Miller, Shelagh AU - Ferguson-Miller S AD - Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd, East Lansing, MI 48824, U.S.A. fergus20@msu.edu. LA - eng GR - R01 GM026916/GM/NIGMS NIH HHS/United States GR - R37 GM026916/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Review DEP - 20170824 PL - England TA - Biochem Soc Trans JT - Biochemical Society transactions JID - 7506897 RN - 0 (Bacterial Proteins) RN - 0 (Ligands) RN - EC 1.9.3.1 (Electron Transport Complex IV) RN - RWP5GA015D (Potassium) SB - IM EIN - Biochem Soc Trans. 2017 Dec 15;45(6):1345. PMID: 29247047 MH - Animals MH - Bacteria/enzymology MH - Bacterial Proteins/chemistry/metabolism MH - Binding Sites MH - Catalytic Domain MH - Crystallography, X-Ray MH - Electron Transport Complex IV/*chemistry/genetics/*metabolism MH - Humans MH - Ligands MH - Models, Molecular MH - Mutation MH - Potassium/*chemistry MH - Protein Structure, Tertiary PMC - PMC6103453 MID - NIHMS983487 OTO - NOTNLM OT - allosteric regulation OT - complex IV OT - conformational change OT - proton pathways COIS- Competing Interests The Authors declare that there are no competing interests associated with the manuscript. EDAT- 2017/08/27 06:00 MHDA- 2018/02/23 06:00 PMCR- 2018/08/21 CRDT- 2017/08/27 06:00 PHST- 2017/06/03 00:00 [received] PHST- 2017/07/14 00:00 [revised] PHST- 2017/07/18 00:00 [accepted] PHST- 2017/08/27 06:00 [pubmed] PHST- 2018/02/23 06:00 [medline] PHST- 2017/08/27 06:00 [entrez] PHST- 2018/08/21 00:00 [pmc-release] AID - BST20160138 [pii] AID - 10.1042/BST20160138 [doi] PST - ppublish SO - Biochem Soc Trans. 2017 Oct 15;45(5):1087-1095. doi: 10.1042/BST20160138. Epub 2017 Aug 24.