Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5B51FJ)

• DOT Name: Dynactin subunit 1 (DCTN1)
• Synonyms: 150 kDa dynein-associated polypeptide; DAP-150; DP-150; p135; p150-glued
• Gene Name: DCTN1
• Related Disease:
  Multiple sclerosis
  Alstrom syndrome
  Amyotrophic lateral sclerosis type 1
  Behavioral variant of frontotemporal dementia
  Depression
  Frontotemporal dementia
  Hereditary motor neuron disease
  Hereditary spastic paraplegia
  Malignant soft tissue neoplasm
  Motor neurone disease
  Neoplasm
  Neuromuscular disease
  Neuronopathy, distal hereditary motor, type 7B
  Perry syndrome
  Progressive supranuclear palsy
  Sarcoma
  Amyotrophic lateral sclerosis
  Autosomal recessive juvenile Parkinson disease 2
  Autosomal recessive limb-girdle muscular dystrophy type 2B
  Juvenile-onset Parkinson disease
  Limb-girdle muscular dystrophy
  Mood disorder
  Pick disease
  Respiratory failure
  Distal hereditary motor neuropathy type 7
  Neurodegenerative disease
  Tauopathy
  Dementia
  Familial spontaneous pneumothorax
  Nervous system disease
  Parkinsonian disorder
• UniProt ID: DCTN1_HUMAN
• PDB ID: 1TXQ; 2COY; 2HKN; 2HKQ; 2HL3; 2HL5; 2HQH; 3E2U; 3TQ7
• Pfam ID: PF01302 ; PF12455
• Sequence:
  MAQSKRHVYSRTPSGSRMSAEASARPLRVGSRVEVIGKGHRGTVAYVGATLFATGKWVGV
  ILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQIQVFEDGADTTSPETPDSSASKVLKRE
  GTDTTAKTSKLRGLKPKKAPTARKTTTRRPKPTRPASTGVAGASSSLGPSGSASAGELSS
  SEPSTPAQTPLAAPIIPTPVLTSPGAVPPLPSPSKEEEGLRAQVRDLEEKLETLRLKRAE
  DKAKLKELEKHKIQLEQVQEWKSKMQEQQADLQRRLKEARKEAKEALEAKERYMEEMADT
  ADAIEMATLDKEMAEERAESLQQEVEALKERVDELTTDLEILKAEIEEKGSDGAASSYQL
  KQLEEQNARLKDALVRMRDLSSSEKQEHVKLQKLMEKKNQELEVVRQQRERLQEELSQAE
  STIDELKEQVDAALGAEEMVEMLTDRNLNLEEKVRELRETVGDLEAMNEMNDELQENARE
  TELELREQLDMAGARVREAQKRVEAAQETVADYQQTIKKYRQLTAHLQDVNRELTNQQEA
  SVERQQQPPPETFDFKIKFAETKAHAKAIEMELRQMEVAQANRHMSLLTAFMPDSFLRPG
  GDHDCVLVLLLMPRLICKAELIRKQAQEKFELSENCSERPGLRGAAGEQLSFAAGLVYSL
  SLLQATLHRYEHALSQCSVDVYKKVGSLYPEMSAHERSLDFLIELLHKDQLDETVNVEPL
  TKAIKYYQHLYSIHLAEQPEDCTMQLADHIKFTQSALDCMSVEVGRLRAFLQGGQEATDI
  ALLLRDLETSCSDIRQFCKKIRRRMPGTDAPGIPAALAFGPQVSDTLLDCRKHLTWVVAV
  LQEVAAAAAQLIAPLAENEGLLVAALEELAFKASEQIYGTPSSSPYECLRQSCNILISTM
  NKLATAMQEGEYDAERPPSKPPPVELRAAALRAEITDAEGLGLKLEDRETVIKELKKSLK
  IKGEELSEANVRLSLLEKKLDSAAKDADERIEKVQTRLEETQALLRKKEKEFEETMDALQ
  ADIDQLEAEKAELKQRLNSQSKRTIEGLRGPPPSGIATLVSGIAGEEQQRGAIPGQAPGS
  VPGPGLVKDSPLLLQQISAMRLHISQLQHENSILKGAQMKASLASLPPLHVAKLSHEGPG
  SELPAGALYRKTSQLLETLNQLSTHTHVVDITRTSPAAKSPSAQLMEQVAQLKSLSDTVE
  KLKDEVLKETVSQRPGATVPTDFATFPSSAFLRAKEEQQDDTVYMGKVTFSCAAGFGQRH
  RLVLTQEQLHQLHSRLIS
• Function: Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules. Plays a key role in dynein-mediated retrograde transport of vesicles and organelles along microtubules by recruiting and tethering dynein to microtubules. Binds to both dynein and microtubules providing a link between specific cargos, microtubules and dynein. Essential for targeting dynein to microtubule plus ends, recruiting dynein to membranous cargos and enhancing dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Can also act as a brake to slow the dynein motor during motility along the microtubule. Can regulate microtubule stability by promoting microtubule formation, nucleation and polymerization and by inhibiting microtubule catastrophe in neurons. Inhibits microtubule catastrophe by binding both to microtubules and to tubulin, leading to enhanced microtubule stability along the axon. Plays a role in metaphase spindle orientation. Plays a role in centriole cohesion and subdistal appendage organization and function. Its recruitment to the centriole in a KIF3A-dependent manner is essential for the maintenance of centriole cohesion and the formation of subdistal appendage. Also required for microtubule anchoring at the mother centriole. Plays a role in primary cilia formation.
• Tissue Specificity: Brain.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Vasopressin-regulated water reabsorption (hsa04962)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  XBP1(S) activates chaperone genes (R-HSA-381038)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Alstrom syndrome	DISFVX55	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Autosomal dominant	[3]
Behavioral variant of frontotemporal dementia	DISQHX2V	Strong	Genetic Variation	[4]
Depression	DIS3XJ69	Strong	Genetic Variation	[5]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[6]
Hereditary motor neuron disease	DIS6XNI0	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[7]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[8]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[10]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[11]
Neuronopathy, distal hereditary motor, type 7B	DISTHV48	Strong	Autosomal dominant	[3]
Perry syndrome	DIS8YKKM	Strong	Autosomal dominant	[3]
Progressive supranuclear palsy	DISO5KRQ	Strong	Genetic Variation	[12]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[8]
Amyotrophic lateral sclerosis	DISF7HVM	Moderate	Autosomal dominant	[13]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	moderate	Biomarker	[14]
Autosomal recessive limb-girdle muscular dystrophy type 2B	DISWWCL7	moderate	Biomarker	[15]
Juvenile-onset Parkinson disease	DISNT5BI	moderate	Biomarker	[14]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Biomarker	[15]
Mood disorder	DISLVMWO	moderate	Biomarker	[14]
Pick disease	DISP6X50	moderate	Genetic Variation	[6]
Respiratory failure	DISVMYJO	moderate	Genetic Variation	[16]
Distal hereditary motor neuropathy type 7	DISJW8SV	Supportive	Autosomal dominant	[17]
Neurodegenerative disease	DISM20FF	Disputed	Genetic Variation	[18]
Tauopathy	DISY2IPA	Disputed	Genetic Variation	[12]
Dementia	DISXL1WY	Limited	Genetic Variation	[4]
Familial spontaneous pneumothorax	DISNM7SU	Limited	Biomarker	[19]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[20]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[12]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Dynactin subunit 1 (DCTN1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynactin subunit 1 (DCTN1).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dynactin subunit 1 (DCTN1).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the expression of Dynactin subunit 1 (DCTN1).	[24]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Dynactin subunit 1 (DCTN1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dynactin subunit 1 (DCTN1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dynactin subunit 1 (DCTN1).	[28]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dynactin subunit 1 (DCTN1).	[26]

References

• [1] The p150 subunit of dynactin (DCTN1) gene in multiple sclerosis.Acta Neurol Scand. 2007 Oct;116(4):231-4. doi: 10.1111/j.1600-0404.2007.00884.x.
• [2] Human DCTN1: genomic structure and evaluation as a candidate for Alstrm syndrome.Genomics. 1998 Nov 1;53(3):359-64. doi: 10.1006/geno.1998.5542.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.JAMA Neurol. 2014 Feb;71(2):208-15. doi: 10.1001/jamaneurol.2013.5100.
• [5] DCTN1 p.K56R in progressive supranuclear palsy.Parkinsonism Relat Disord. 2016 Jul;28:56-61. doi: 10.1016/j.parkreldis.2016.04.025. Epub 2016 Apr 23.
• [6] Distal hereditary motor neuropathy type7B with Dynactin 1 mutation.Mol Med Rep. 2016 Oct;14(4):3362-8. doi: 10.3892/mmr.2016.5664. Epub 2016 Aug 22.
• [7] Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.Clin Genet. 2016 Aug;90(2):127-33. doi: 10.1111/cge.12712. Epub 2016 Feb 16.
• [8] ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.J Pathol. 2017 Feb;241(3):316-323. doi: 10.1002/path.4836. Epub 2016 Dec 15.
• [9] Autophagy and Ubiquitin-Proteasome System Coordinate to Regulate the Protein Quality Control of Neurodegenerative Disease-Associated DCTN1.Neurotox Res. 2020 Jan;37(1):48-57. doi: 10.1007/s12640-019-00113-y. Epub 2019 Oct 25.
• [10] STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.J Hematol Oncol. 2015 Jun 11;8:66. doi: 10.1186/s13045-015-0160-2.
• [11] Mouse p150Glued (dynactin 1) cDNA sequence and evaluation as a candidate for the neuromuscular disease mutation mnd2.Biochem Biophys Res Commun. 1997 Feb 13;231(2):344-7. doi: 10.1006/bbrc.1997.6095.
• [12] DCTN1 F52L mutation case of Perry syndrome with progressive supranuclear palsy-like tauopathy.Parkinsonism Relat Disord. 2018 Jun;51:105-110. doi: 10.1016/j.parkreldis.2018.02.038. Epub 2018 Feb 23.
• [13] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [14] DCTN1 mutations in Perry syndrome.Nat Genet. 2009 Feb;41(2):163-5. doi: 10.1038/ng.293. Epub 2009 Jan 11.
• [15] The genomic structure of DCTN1, a candidate gene for limb-girdle muscular dystrophy (LGMD2B).Biochim Biophys Acta. 1998 Nov 8;1442(2-3):432-6. doi: 10.1016/s0167-4781(98)00195-x.
• [16] Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure.Mov Disord. 2010 Apr 30;25(6):767-70. doi: 10.1002/mds.22950.
• [17] Mutant dynactin in motor neuron disease. Nat Genet. 2003 Apr;33(4):455-6. doi: 10.1038/ng1123. Epub 2003 Mar 10.
• [18] The G59S mutation in p150(glued) causes dysfunction of dynactin in mice.J Neurosci. 2007 Dec 19;27(51):13982-90. doi: 10.1523/JNEUROSCI.4226-07.2007.
• [19] PBB3 imaging in Parkinsonian disorders: Evidence for binding to tau and other proteins.Mov Disord. 2017 Jul;32(7):1016-1024. doi: 10.1002/mds.27029. Epub 2017 Jun 1.
• [20] Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases.Biochem Soc Trans. 2013 Dec;41(6):1605-12. doi: 10.1042/BST20130188.
• [21] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [24] Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells. Mol Biosyst. 2012 Apr;8(4):1078-87. doi: 10.1039/c2mb05486h. Epub 2012 Jan 10.
• [25] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.