| Structural highlights
Function
[LONM_HUMAN] ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix. May also have a chaperone function in the assembly of inner membrane protein complexes. Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single-stranded, site-specific, and strand-specific manner. May regulate mitochondrial DNA replication and/or gene expression using site-specific, single-stranded DNA binding to target the degradation of regulatory proteins binding to adjacent sites in mitochondrial promoters. Endogenous substrates include mitochondrial steroidogenic acute regulatory (StAR) protein.[HAMAP-Rule:MF_03120][1] [2] [3] [4]
Publication Abstract from PubMed
LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.
Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology.,Kingsley LJ, He X, McNeill M, Nelson J, Nikulin V, Ma Z, Lu W, Zhou VW, Manuia M, Kreusch A, Gao MY, Witmer D, Vaillancourt MT, Lu M, Greenblatt S, Lee C, Vashisht A, Bender S, Spraggon G, Michellys PY, Jia Y, Haling JR, Lelais G J Med Chem. 2021 Apr 6. doi: 10.1021/acs.jmedchem.0c02152. PMID:33821636[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bota DA, Davies KJ. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol. 2002 Sep;4(9):674-80. PMID:12198491 doi:http://dx.doi.org/10.1038/ncb836
- ↑ Ondrovicova G, Liu T, Singh K, Tian B, Li H, Gakh O, Perecko D, Janata J, Granot Z, Orly J, Kutejova E, Suzuki CK. Cleavage site selection within a folded substrate by the ATP-dependent lon protease. J Biol Chem. 2005 Jul 1;280(26):25103-10. Epub 2005 May 3. PMID:15870080 doi:http://dx.doi.org/10.1074/jbc.M502796200
- ↑ Lu B, Yadav S, Shah PG, Liu T, Tian B, Pukszta S, Villaluna N, Kutejova E, Newlon CS, Santos JH, Suzuki CK. Roles for the human ATP-dependent Lon protease in mitochondrial DNA maintenance. J Biol Chem. 2007 Jun 15;282(24):17363-74. Epub 2007 Apr 9. PMID:17420247 doi:http://dx.doi.org/10.1074/jbc.M611540200
- ↑ Wang N, Gottesman S, Willingham MC, Gottesman MM, Maurizi MR. A human mitochondrial ATP-dependent protease that is highly homologous to bacterial Lon protease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11247-51. PMID:8248235
- ↑ Kingsley LJ, He X, McNeill M, Nelson J, Nikulin V, Ma Z, Lu W, Zhou VW, Manuia M, Kreusch A, Gao MY, Witmer D, Vaillancourt MT, Lu M, Greenblatt S, Lee C, Vashisht A, Bender S, Spraggon G, Michellys PY, Jia Y, Haling JR, Lelais G. Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology. J Med Chem. 2021 Apr 6. doi: 10.1021/acs.jmedchem.0c02152. PMID:33821636 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02152
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