6x1m

From Proteopedia

(Difference between revisions)

Revision as of 14:40, 18 October 2023

Lon protease proteolytic domain complexed with covalent boronic acid inhibitor

Structural highlights

6x1m is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.51Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6x1m"

Categories: Homo sapiens | Large Structures | Lee CC | Spraggon G

@@ Line 3: / Line 3: @@
 <StructureSection load='6x1m' size='340' side='right'caption='[[6x1m]], [[Resolution|resolution]] 3.51&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6x1m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X1M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6x1m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X1M FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UKS:[(1R)-4-phenyl-1-{[N-(pyrazine-2-carbonyl)-D-norvalyl]amino}butyl]boronic+acid'>UKS</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.51&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6wzv|6wzv]], [[6wys|6wys]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UKS:[(1R)-4-phenyl-1-{[N-(pyrazine-2-carbonyl)-D-norvalyl]amino}butyl]boronic+acid'>UKS</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LONP1, PRSS15 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Endopeptidase_La Endopeptidase La], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.53 3.4.21.53] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6x1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x1m OCA], [https://pdbe.org/6x1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x1m RCSB], [https://www.ebi.ac.uk/pdbsum/6x1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x1m ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/LONM_HUMAN 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]<ref>PMID:12198491</ref> <ref>PMID:15870080</ref> <ref>PMID:17420247</ref> <ref>PMID:8248235</ref>
+[https://www.uniprot.org/uniprot/LONM_HUMAN 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]<ref>PMID:12198491</ref> <ref>PMID:15870080</ref> <ref>PMID:17420247</ref> <ref>PMID:8248235</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Endopeptidase La]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Lee, C C]]
+[[Category: Lee CC]]
-[[Category: Spraggon, G]]
+[[Category: Spraggon G]]
-[[Category: Covalent inhibitor]]
-[[Category: Hydrolase]]
-[[Category: Proteolytic domain]]

6x1m

From Proteopedia

Revision as of 14:40, 18 October 2023

Lon protease proteolytic domain complexed with covalent boronic acid inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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