A New Inhibitor of ADAM17 Composed of a Zinc-Binding Dithiol Moiety and a Specificity Pocket-Binding Appendage

Tateishi, Hiroshi; Tateishi, Mika; Radwan, Mohamed O.; Masunaga, Takuya; Kawatashiro, Kosuke; Oba, Yasunori; Oyama, Misato; Inoue-Kitahashi, Natsuki; Fujita, Mikako; Okamoto, Yoshinari; Otsuka, Masami

doi:10.1248/cpb.c21-00701

Cited by 14 publications

(9 citation statements)

References 38 publications

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“…Then, we also reported that SN-1 bound to TRAF6 suppressing its auto-ubiquitination and downstream NF-κB signaling supported by the molecular docking studies exhibiting that SN-1 interacted with the first zinc finger of TRAF6 [51]. Besides, we further demonstrated that SN-1 derivatives hold promise for developing new drug candidates targeting zinc proteins [54]. In future studies, we plan to perform structural studies of TRAF6 with SN-1.…”

Section: Discussionmentioning

confidence: 91%

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Güven

Çi̇ftçi̇

Tateishi

et al. 2023

Preprint

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Tumor Necrosis Factor Receptor Associated Factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system (CNS), and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. RING domain and zinc fingers mediate the activation of nuclear factor kappa B (NF-kB), which has essential roles in the regulation of inflammatory responses, proliferation, differentiation, migration, cell adhesion, and apoptosis. Therefore, it has been found that TRAF6 is overexpressed in various types of cancer including pancreatic, liver, lung, head and neck, breast, colorectal cancers, and melanoma along with inflammatory, autoimmune and neurodegenerative disorders. Furthermore, TRAF6 is an important therapeutic target for numerous disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we present a TRAF6 N-terminal structure determined at the Turkish Light Source Turkish DeLight to 2.6 A; resolution at cryogenic temperature. This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research.

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Section: Discussionmentioning

confidence: 91%

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Güven

Çi̇ftçi̇

Tateishi

et al. 2023

Preprint

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“…The docking study was conducted using the rigid-receptor method. 69,70 The co-crystallized ligand B48 was dened as the center of the binding site. Using the MOE build suite, the chemical structures were drawn, and then energy-minimized using the MOE default force eld.…”

Section: Discussionmentioning

confidence: 99%

Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure–activity relationship, activity profile, mode of action, and molecular docking

et al. 2022

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“…The crystal structure of myr‐MA (PDB code: 1UPH) (Tang et al., 2004) was obtained from the Protein Data Bank. Both 1UPH and the evaluated ligands were prepared, and the docking process was performed using the default parameters of MOE 2019.01, as previously described (Hamdy et al., 2022; Tateishi et al., 2021). The compounds were docked into the active site using a rigid receptor docking protocol, where ligand conformations were placed onto the active site dummy atoms using the Triangle Matcher method, with the AMBER10 force field employed as the default.…”

Section: Methodsmentioning

confidence: 99%

HIV‐1 Gag MA domain binds to cardiolipin in a binding mode distinct from virus assemble mediator PI(4,5)P₂

Tateishi,

Chinen,

Fukuda

et al. 2023

Chem Biol Drug Des

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The human immunodeficiency virus type 1 (HIV‐1) Gag protein is responsible for facilitating HIV‐1 virion assembly and budding. Our study demonstrates that cardiolipin (CL), a component found in the inner mitochondrial membrane, exhibits the highest binding affinity to the N‐terminal MA domain of the HIV‐1 Gag protein within the lipid group of host cells. To assess this binding interaction, we synthesized short acyl chain derivatives of CL and employed surface plasmon resonance (SPR) analysis to determine the dissociation constants (Kd) for CL and the MA domain. Simultaneously, we examined the Kd of D‐myo‐phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P2) derivatives, known to play a crucial role in virion formation. Among all the derivatives, Tetra‐C7‐CL exhibited the lowest Kd value (Kd = 30.8 ± 6.9 μM) for MA binding on the CL analog‐immobilized sensorchip, indicating a higher affinity. Similarly, the Kd value of Di‐C7‐PIP2 (Kd = 36.6 ± 4.7 μM) was the lowest on the PI(4,5)P2 analog‐immobilized sensorchip. Thus, Tetra‐C7‐CL binds to the MA domain using a distinct binding mode while displaying a comparable binding affinity to Di‐C7‐PIP2. This discovery holds significant implications for comprehending the virological importance of CL–MA domain binding, such as its subcellular distribution, including mitochondrial translocation, and involvement in viral particle formation in concert with PI(4,5)P2. Furthermore, this study has the potential to contribute to the development of drugs in the future.

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A New Inhibitor of ADAM17 Composed of a Zinc-Binding Dithiol Moiety and a Specificity Pocket-Binding Appendage

Cited by 14 publications

References 38 publications

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure–activity relationship, activity profile, mode of action, and molecular docking

HIV‐1 Gag MA domain binds to cardiolipin in a binding mode distinct from virus assemble mediator PI(4,5)P₂

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A New Inhibitor of ADAM17 Composed of a Zinc-Binding Dithiol Moiety and a Specificity Pocket-Binding Appendage

Cited by 14 publications

References 38 publications

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure–activity relationship, activity profile, mode of action, and molecular docking

HIV‐1 Gag MA domain binds to cardiolipin in a binding mode distinct from virus assemble mediator PI(4,5)P2

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HIV‐1 Gag MA domain binds to cardiolipin in a binding mode distinct from virus assemble mediator PI(4,5)P₂