Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| Target ID |
T92678
|
|||||
| Target Name |
MALT lymphoma-associated translocation (MALT1)
|
|||||
| Synonyms |
MALT lymphoma-associated translocation; Paracaspase
Click to Show/Hide
|
|||||
| Gene Name |
MALT1
|
|||||
| Target Type |
Clinical trial target
|
[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 2 | Mature B-cell leukaemia [ICD-11: 2A82] | |||||
| Function |
Protease that enhances BCL10-induced activation of NF-kappa-B by mediating its cleavage. MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion. Involved in the induction of T helper 17 cells (Th17) differentiation. Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (By similarity). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation. Also has ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity.
Click to Show/Hide
|
|||||
| BioChemical Class |
Peptidase
|
|||||
| UniProt ID | ||||||
| EC Number |
EC 3.4.22.-
|
|||||
| Sequence |
MSLLGDPLQALPPSAAPTGPLLAPPAGATLNRLREPLLRRLSELLDQAPEGRGWRRLAEL
AGSRGRLRLSCLDLEQCSLKVLEPEGSPSLCLLKLMGEKGCTVTELSDFLQAMEHTEVLQ LLSPPGIKITVNPESKAVLAGQFVKLCCRATGHPFVQYQWFKMNKEIPNGNTSELIFNAV HVKDAGFYVCRVNNNFTFEFSQWSQLDVCDIPESFQRSVDGVSESKLQICVEPTSQKLMP GSTLVLQCVAVGSPIPHYQWFKNELPLTHETKKLYMVPYVDLEHQGTYWCHVYNDRDSQD SKKVEIIIGRTDEAVECTEDELNNLGHPDNKEQTTDQPLAKDKVALLIGNMNYREHPKLK APLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLLDKGVYGLLYYAGHGYENF GNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDAL KVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKCH LTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQI QLGFAAEFSNVMIIYTSIVYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVS KDLPKHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRG LGRKTCFQTCLMSNGPYQSSAATSGGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCS RTPDAFISSFAHHASCHFSRSNVPVETTDEIPFSFSDRLRISEK Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | JNJ-67856633 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | JNJ-67856633 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Nvs-malt1 | Ligand Info | |||||
| Structure Description | MALT1 in complex with a NVS-MALT1 chemical probe | PDB:7A41 | ||||
| Method | X-ray diffraction | Resolution | 2.13 Å | Mutation | No | [3] |
| PDB Sequence |
QPLAKDKVAL
346 LIGNMNYREH356 PKLKAPLVDV366 YELTNLLRQL376 DFKVVSLLDL386 TEYEMRNAVD 396 EFLLLLDKGV406 YGLLYYAGHG416 YENFGNSFMV426 PVDAPNPYRS436 ENCLCVQNIL 446 KLMQEKETGL456 NVFLLDMCRT483 ANIVFGYATC493 QGGLANGIFM512 KFLKDRLLED 522 KKITVLLDEV532 AEDMGKCHLT542 KGKQALEIRS552 SLSEKRALTD562 PIQGTEYSAE 572 SLVRNLQWAK582 AHELPESMCL592 KFDCGVQIQL602 GFAAEFSNVM612 IIYTSIVYKP 622 PEIIMCDAYV632 TDFPLDLDID642 PKDANKGTPE652 ETGSYLVSKD662 LPKHCLYTRL 672 SSLQKLKEHL682 VFTVCLSYQY692 SGLEDTVEDK702 QEVNVGKPLI712 AKLD |
|||||
|
|
VAL344
3.904
ALA345
3.470
LEU346
3.724
LYS379
3.126
VAL380
4.164
VAL381
3.498
LEU383
3.536
LEU386
3.270
TYR389
3.078
GLU390
3.090
MET391
4.641
ASN393
2.986
ALA394
3.401
|
|||||
| Ligand Name: 1-[4-[4-(aminomethyl)pyrazol-1-yl]-3-chloranyl-phenyl]-3-[(3~{R})-6-bromanyl-3,4-dihydro-2~{H}-chromen-3-yl]urea | Ligand Info | |||||
| Structure Description | Human MALT1(329-729) in complex with a chromane urea containing inhibitor | PDB:7AK0 | ||||
| Method | X-ray diffraction | Resolution | 2.32 Å | Mutation | No | [4] |
| PDB Sequence |
QPLAKDKVAL
346 LIGNMNYREH356 PKLKAPLVDV366 YELTNLLRQL376 DFKVVSLLDL386 TEYEMRNAVD 396 EFLLLLDKGV406 YGLLYYAGHG416 YENFGNSFMV426 PVDAPNPYRS436 ENCLCVQNIL 446 KLMQEKETGL456 NVFLLDMCRV482 TANIVFGYAT492 CQGLANGIFM512 KFLKDRLLED 522 KKITVLLDEV532 AEDMGKCHLT542 QALEIRSSLS555 EKRALTDPIQ565 EYSAESLVRN 577 LQWAKAHELP587 ESMCLKFDCG597 VQIQLGFAAE607 FSNVMIIYTS617 IVYKPPEIIM 627 CDAYVTDFPL637 DLDIDPKDAN647 KGTPEETGSY657 LVSKDLPKHC667 LYTRLSSLQK 677 LKEHLVFTVC687 LSYQYSGLED697 TVEDKQEVNV707 GKPLIAKLDM717 HRGLG |
|||||
|
|
VAL344
4.242
ALA345
3.423
LEU346
3.632
LYS379
3.826
VAL380
4.854
VAL381
3.721
LEU383
3.566
LEU386
4.106
THR387
4.684
TYR389
4.022
GLU390
2.599
ASN393
2.840
ALA394
3.398
GLU397
3.012
|
|||||
| 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
|
|
|
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 |
|---|---|---|---|
| NF-kappa B signaling pathway | hsa04064 | Affiliated Target |
|
| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| C-type lectin receptor signaling pathway | hsa04625 | Affiliated Target |
|
| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| T cell receptor signaling pathway | hsa04660 | Affiliated Target |
|
| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| B cell receptor signaling pathway | hsa04662 | Affiliated Target |
|
| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 11 | Degree centrality | 1.18E-03 | Betweenness centrality | 1.08E-04 |
|---|---|---|---|---|---|
| Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 6.18E-01 |
| Neighborhood connectivity | 3.85E+01 | Topological coefficient | 1.88E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | National Cancer Institute Drug Dictionary (drug name JNJ67856633). | |||||
| REF 2 | ClinicalTrials.gov (NCT03900598) A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL). U.S. National Institutes of Health. | |||||
| REF 3 | MALT1 in complex with a NVS-MALT1 chemical probe | |||||
| REF 4 | Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing. J Med Chem. 2020 Dec 10;63(23):14576-14593. | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.