Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives

Guven, Omur; Sever, Belgin; Başoğlu-Ünal, Faika; Ece, Abdulilah; Tateishi, Hiroshi; Koga, Ryoko; Radwan, Mohamed O.; Demir, Nefise; Can, Mustafa; Dilsiz Aytemir, Mutlu; Inoue, Jun-ichiro; Otsuka, Masami; Fujita, Mikako; Ciftci, Halilibrahim; DeMirci, Hasan

doi:10.3390/ph16111608

Title: Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives

Journal Article · 13 November 2023 · Pharmaceuticals

DOI: https://doi.org/10.3390/ph16111608 · OSTI ID:2327002

Guven, Omur ^[1];

^[2];

^[3];

^[4];

^[5]; Koga, Ryoko ^[5];

^[5]; Demir, Nefise ^[6]; Can, Mustafa ^[6]; Dilsiz Aytemir, Mutlu ^[7];

^[8]; Otsuka, Masami ^[9];

^[5];

^[10];

^[11]

Koç University, Istanbul (Turkey); SLAC
Kumamoto University (Japan); Anadolu University, Eskisehir (Turkey)
European University of Lefke, Northern Cyprus, Mersin (Turkey)
Biruni University, Istanbul (Turkey)
Kumamoto University (Japan)
Izmir Katip Celebi University, Izmir (Turkey)
Izmir Katip Celebi University, Izmir (Turkey); Hacettepe University, Ankara (Turkey)
University of Tokyo (Japan)
Kumamoto University (Japan); Science Farm Ltd., Kumamoto (Japan)
Koç University, Istanbul (Turkey); Kumamoto University (Japan); Science Farm Ltd., Kumamoto (Japan)
Koç University, Istanbul (Turkey); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

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, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source “Turkish DeLight” to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). 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. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); TÜBİTAK 1001

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2327002

Journal Information:: Pharmaceuticals, Journal Name: Pharmaceuticals Journal Issue: 11 Vol. 16; ISSN 1424-8247

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
TRAF6
zinc finger
RING domain
cancer
x-ray crystallography
structural biology
Turkish light source “Turkish DeLight”
molecular modelling
pharmacokinetic determinants

Title: Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives

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