Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| Target ID |
T68470
(Former ID: TTDI03610)
|
|||||
| Target Name |
Deubiquitinating enzyme 1 (USP1)
|
|||||
| Synonyms |
hUBP; Ubiquitin-specific-processing protease 1; Ubiquitin thioesterase 1; Ubiquitin carboxyl-terminal hydrolase 1
Click to Show/Hide
|
|||||
| Gene Name |
USP1
|
|||||
| Target Type |
Literature-reported target
|
[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Involved in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA. Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity. Negative regulator of DNA damage repair which specifically deubiquitinates monoubiquitinated FANCD2.
Click to Show/Hide
|
|||||
| BioChemical Class |
Peptidase
|
|||||
| UniProt ID | ||||||
| EC Number |
EC 3.4.19.12
|
|||||
| Sequence |
MPGVIPSESNGLSRGSPSKKNRLSLKFFQKKETKRALDFTDSQENEEKASEYRASEIDQV
VPAAQSSPINCEKRENLLPFVGLNNLGNTCYLNSILQVLYFCPGFKSGVKHLFNIISRKK EALKDEANQKDKGNCKEDSLASYELICSLQSLIISVEQLQASFLLNPEKYTDELATQPRR LLNTLRELNPMYEGYLQHDAQEVLQCILGNIQETCQLLKKEEVKNVAELPTKVEEIPHPK EEMNGINSIEMDSMRHSEDFKEKLPKGNGKRKSDTEFGNMKKKVKLSKEHQSLEENQRQT RSKRKATSDTLESPPKIIPKYISENESPRPSQKKSRVKINWLKSATKQPSILSKFCSLGK ITTNQGVKGQSKENECDPEEDLGKCESDNTTNGCGLESPGNTVTPVNVNEVKPINKGEEQ IGFELVEKLFQGQLVLRTRCLECESLTERREDFQDISVPVQEDELSKVEESSEISPEPKT EMKTLRWAISQFASVERIVGEDKYFCENCHHYTEAERSLLFDKMPEVITIHLKCFAASGL EFDCYGGGLSKINTPLLTPLKLSLEEWSTKPTNDSYGLFAVVMHSGITISSGHYTASVKV TDLNSLELDKGNFVVDQMCEIGKPEPLNEEEARGVVENYNDEEVSIRVGGNTQPSKVLNK KNVEAIGLLGGQKSKADYELYNKASNPDKVASTAFAENRNSETSDTTGTHESDRNKESSD QTGINISGFENKISYVVQSLKEYEGKWLLFDDSEVKVTEEKDFLNSLSPSTSPTSTPYLL FYKKL Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | ML323 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | ML323 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: ML323 | Ligand Info | |||||
| Structure Description | USP1 bound to ML323 and ubiquitin conjugated to FANCD2 (focused refinement) | PDB:7ZH4 | ||||
| Method | Electron microscopy | Resolution | 2.49 Å | Mutation | Yes | [3] |
| PDB Sequence |
GLNNLGNTSY
91 LNSILQVLYF101 CPGFKSGVKH111 LFNIISRKKY143 ELICSLQSLI153 ISVEQLQASF 163 LLNPLQHDAQ201 EVLQCILGNI211 QETCQLLKKG422 FELVEKLFQG432 QLVLRTRCLE 442 CESLTERRED452 FQDISVPVQE462 DMKTLRWAIS490 QFASVERIVG500 EDKYFCENCH 510 HYTEAERSLL520 FDKMPEVITI530 HLKCFAASGL549 SKINTPLLTP559 LKLSLEEWST 569 KPTNDSYGLF579 AVVMHSGITI589 SSGHYTASVK599 VTYEGKWLLF750 DDSEVKVTEE 760 KDFLNSLSPS770 TSPTSTPYLL780 FYKKL
|
|||||
|
|
||||||
| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Allylamine | Ligand Info | |||||
| Structure Description | Crystal structure of truncated USP1-UAF1 reacted with ubiquitin-prg | PDB:7AY2 | ||||
| Method | X-ray diffraction | Resolution | 3.20 Å | Mutation | No | [4] |
| PDB Sequence |
ENLLPFVGLN
84 NLGNTCYLNS94 ILQVLYFCPG104 FKSGVKHLFN114 IISRKKLASY143 ELICSLQSLI 153 ISVEQLQASF163 LLNPEKYTDE173 LATQPRRLLN183 TLRELNPMYE193 GYLQHDAQEV 203 LQCILGNIQE213 TCQLLKKEEV223 KNIGFELVEK428 LFQGQLVLRT438 RCLECESLTE 448 RREDFQDISV458 PVQEDEMKTL485 RWAISQFASV495 ERIVGEDKYF505 CENCHHYTEA 515 ERSLLFDKMP525 EVITIHLKCF535 AASGLGGLSK551 INTPLLTPLK561 LSLEEWSTKP 571 TNDSYGLFAV581 VMHSGITISS591 GHYTASVKVT601 DEQSLKEYEG745 KWLLFDDSEV 755 KVTEEKDFLN765 SLSPPTSTPY778 LLFYKKL
|
|||||
|
|
||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
|---|---|
|
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 Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
|
|
|
There is no similarity protein (E value < 0.005) for this target
|
|
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.
|
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
|---|---|---|---|
| Fanconi anemia pathway | hsa03460 | Affiliated Target |
|
| Class: Genetic Information Processing => Replication and repair | Pathway Hierarchy | ||
| Degree | 16 | Degree centrality | 1.72E-03 | Betweenness centrality | 2.00E-05 |
|---|---|---|---|---|---|
| Closeness centrality | 2.04E-01 | Radiality | 1.35E+01 | Clustering coefficient | 6.83E-01 |
| Neighborhood connectivity | 2.68E+01 | Topological coefficient | 1.86E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
|---|---|
| Target Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-interacting Proteins | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | Synthesis and structure-activity relationship studies of N-benzyl-2-phenylpyrimidin-4-amine derivatives as potent USP1/UAF1 deubiquitinase inhibitors with anticancer activity against nonsmall cell lung cancer. J Med Chem. 2014 Oct 9;57(19):8099-110. | |||||
| REF 2 | Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2018 Jan;17(1):57-78. | |||||
| REF 3 | Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. Sci Adv. 2022 Sep 30;8(39):eabq6353. | |||||
| REF 4 | Structural basis of FANCD2 deubiquitination by USP1-UAF1. Nat Struct Mol Biol. 2021 Apr;28(4):356-364. | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.