Target Information
| Target General Information | Top | |||||
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| Target ID |
T86773
(Former ID: TTDNR00701)
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| Target Name |
ATP-dependent protease Lon (LONP1)
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| Synonyms |
Serine protease 15; Mitochondrial ATP-dependent protease Lon; Lon protease-like protein; LONP1; LONP; LONHs
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| Gene Name |
LONP1
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
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.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.53
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| Sequence |
MAASTGYVRLWGAARCWVLRRPMLAAAGGRVPTAAGAWLLRGQRTCDASPPWALWGRGPA
IGGQWRGFWEASSRGGGAFSGGEDASEGGAEEGAGGAGGSAGAGEGPVITALTPMTIPDV FPHLPLIAITRNPVFPRFIKIIEVKNKKLVELLRRKVRLAQPYVGVFLKRDDSNESDVVE SLDEIYHTGTFAQIHEMQDLGDKLRMIVMGHRRVHISRQLEVEPEEPEAENKHKPRRKSK RGKKEAEDELSARHPAELAMEPTPELPAEVLMVEVENVVHEDFQVTEEVKALTAEIVKTI RDIIALNPLYRESVLQMMQAGQRVVDNPIYLSDMGAALTGAESHELQDVLEETNIPKRLY KALSLLKKEFELSKLQQRLGREVEEKIKQTHRKYLLQEQLKIIKKELGLEKDDKDAIEEK FRERLKELVVPKHVMDVVDEELSKLGLLDNHSSEFNVTRNYLDWLTSIPWGKYSNENLDL ARAQAVLEEDHYGMEDVKKRILEFIAVSQLRGSTQGKILCFYGPPGVGKTSIARSIARAL NREYFRFSVGGMTDVAEIKGHRRTYVGAMPGKIIQCLKKTKTENPLILIDEVDKIGRGYQ GDPSSALLELLDPEQNANFLDHYLDVPVDLSKVLFICTANVTDTIPEPLRDRMEMINVSG YVAQEKLAIAERYLVPQARALCGLDESKAKLSSDVLTLLIKQYCRESGVRNLQKQVEKVL RKSAYKIVSGEAESVEVTPENLQDFVGKPVFTVERMYDVTPPGVVMGLAWTAMGGSTLFV ETSLRRPQDKDAKGDKDGSLEVTGQLGEVMKESARIAYTFARAFLMQHAPANDYLVTSHI HLHVPEGATPKDGPSAGCTIVTALLSLAMGRPVRQNLAMTGEVSLTGKILPVGGIKEKTI AAKRAGVTCIVLPAENKKDFYDLAAFITEGLEVHFVEHYREIFDIAFPDEQAEALAVER Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Adenosine triphosphate | Ligand Info | |||||
| Structure Description | Human mitochondrial Lon protease with substrate in the ATPase domain | PDB:7P09 | ||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | No | [2] |
| PDB Sequence |
EKDDKDAIEE
419 KFRERLKELV429 VPKHVMDVVD439 EELSKLGLLD449 NHSSEFNVTR459 NYLDWLTSIP 469 WGKYSNENLD479 LARAQAVLEE489 DHYGMEDVKK499 RILEFIAVSQ509 LRGSTQGKIL 519 CFYGPPGVGK529 TSIARSIARA539 LNREYFRFSV549 GGMTDVAEIK559 GHRRTYVGAM 569 PGKIIQCLKK579 TKTENPLILI589 DEVDKIGRGY599 QGDPSSALLE609 LLDPEQNANF 619 LDHYLDVPVD629 LSKVLFICTA639 NVTDTIPEPL649 RDRMEMINVS659 GYVAQEKLAI 669 AERYLVPQAR679 ALCGLDESKA689 KLSSDVLTLL699 IKQYCRESGV709 RNLQKQVEKV 719 LRKSAYKIVS729 GEAESVEVTP739 ENLQDFVGKP749 VFTVERMYDV759 TPPGVVMGLA 769 WTAMGGSTLF779 VETSLRRPGD795 KDGSLEVTGQ805 LGEVMKESAR815 IAYTFARAFL 825 MQHAPANDYL835 VTSHIHLHVP845 EGATPKDGPS855 AGCTIVTALL865 SLAMGRPVRQ 875 NLAMTGEVSL885 TGKILPVGGI895 KEKTIAAKRA905 GVTCIVLPAE915 NKKDFYDLAA 925 FITEGLEVHF935 VEHYREIFDI945 AFPD
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ASP490
4.286
HIS491
3.748
TYR492
2.703
GLY493
4.929
MET494
3.997
PRO524
3.979
PRO525
3.266
GLY526
2.845
VAL527
3.006
GLY528
2.968
LYS529
2.895
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Bortezomib | Ligand Info | |||||
| Structure Description | Lon protease proteolytic domain complexed with bortezomib | PDB:6X27 | ||||
| Method | X-ray diffraction | Resolution | 2.12 Å | Mutation | No | [3] |
| PDB Sequence |
ERMYDVTPPG
763 VVMGLAWTAM773 GGSTLFVETS783 LRRPDGSLEV802 TGQLGEVMKE812 SARIAYTFAR 822 AFLMQHAPAN832 DYLVTSHIHL842 HVPEGATPKD852 GPSAGCTIVT862 ALLSLAMGRP 872 VRQNLAMTGE882 VSLTGKILPV892 GGIKEKTIAA902 KRAGVTCIVL912 PAENKKDFYD 922 LAAFITEGLE932 VHFVEHYREI942 FDIAFP
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Similarity Proteins
Human Tissue Distribution
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
|---|---|---|---|
| Caseinolytic peptidase B protein homolog (CLPB) | 26.623 (41/154) | 7.00E-04 |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| References | Top | |||||
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| REF 1 | Inhibition of LONP1 Suppresses Pancreatic Cancer Progression Via c-Jun N-Terminal Kinase Pathway-Meditated Epithelial-Mesenchymal Transition. Pancreas. 2019 May/Jun;48(5):629-635. | |||||
| REF 2 | A dual allosteric pathway drives human mitochondrial Lon | |||||
| REF 3 | Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology. J Med Chem. 2021 Apr 22;64(8):4857-4869. | |||||
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