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Structural characterization of TRAF6 N-terminal for therapeutic uses and computational studies on new derivatives

dc.contributor.coauthorSever, Belgin
dc.contributor.coauthorBasoglu-Unal, Faika
dc.contributor.coauthorEce, Abdulilah
dc.contributor.coauthorTateishi, Hiroshi
dc.contributor.coauthorKoga, Ryoko
dc.contributor.coauthorRadwan, Mohamed O.
dc.contributor.coauthorDemir, Nefise
dc.contributor.coauthorCan, Mustafa
dc.contributor.coauthorAytemir, Mutlu Dilsiz
dc.contributor.coauthorInoue, Jun-ichiro
dc.contributor.coauthorOtsuka, Masami
dc.contributor.coauthorFujita, Mikako
dc.contributor.departmentDepartment of Molecular Biology and Genetics
dc.contributor.departmentKUISCID (Koç University İşbank Center for Infectious Diseases)
dc.contributor.departmentGraduate School of Sciences and Engineering
dc.contributor.kuauthorDemirci, Hasan
dc.contributor.kuauthorÇiftçi, Halil İbrahim
dc.contributor.kuauthorGüven, Ömür
dc.contributor.schoolcollegeinstituteCollege of Sciences
dc.contributor.schoolcollegeinstituteGRADUATE SCHOOL OF SCIENCES AND ENGINEERING
dc.contributor.schoolcollegeinstituteResearch Center
dc.date.accessioned2025-01-19T10:30:12Z
dc.date.issued2023
dc.description.abstractTumor 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 angstrom 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.
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue11
dc.description.openaccessGreen Published, gold
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipAuthors would like to dedicate this manuscript to the memory of Albert E. Dahlberg and Nizar Turker. The authors gratefully acknowledge the use of the services and Turkish Light Source (Turkish DeLight) X-ray facility at the University of Health Sciences, Experimental Medicine Application & Research Center, Validebag Research Park. Coordinates of the TRAF6 N-terminal structure have been deposited in the Protein Data Bank under accession codes 8HZ2.
dc.description.volume16
dc.identifier.doi10.3390/ph16111608
dc.identifier.eissn1424-8247
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85178372037
dc.identifier.urihttps://doi.org/10.3390/ph16111608
dc.identifier.urihttps://hdl.handle.net/20.500.14288/26008
dc.identifier.wos1114535900001
dc.keywordsTRAF6
dc.keywordsZinc finger
dc.keywordsRING domain
dc.keywordsCancer
dc.keywordsX-ray crystallography
dc.keywordsStructural biology
dc.keywordsTurkish light source "Turkish DeLight"
dc.keywordsMolecular modelling
dc.keywordsPharmacokinetic determinants
dc.language.isoeng
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.relation.grantnoTBIdot;TAK 1001 program
dc.relation.ispartofPharmaceuticals
dc.subjectChemistry, medicinal
dc.subjectPharmacology and pharmacy
dc.titleStructural characterization of TRAF6 N-terminal for therapeutic uses and computational studies on new derivatives
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorDemirci, Hasan
local.contributor.kuauthorGüven, Ömür
local.contributor.kuauthorÇiftçi, Halil İbrahim
local.publication.orgunit1College of Sciences
local.publication.orgunit1GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
local.publication.orgunit1Research Center
local.publication.orgunit2Department of Molecular Biology and Genetics
local.publication.orgunit2KUISCID (Koç University İşbank Center for Infectious Diseases)
local.publication.orgunit2Graduate School of Sciences and Engineering
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