Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/11/1608 |
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| author | Omur Guven Belgin Sever Faika Başoğlu-Ünal Abdulilah Ece Hiroshi Tateishi Ryoko Koga Mohamed O. Radwan Nefise Demir Mustafa Can Mutlu Dilsiz Aytemir Jun-ichiro Inoue Masami Otsuka Mikako Fujita Halilibrahim Ciftci Hasan DeMirci |
| author_facet | Omur Guven Belgin Sever Faika Başoğlu-Ünal Abdulilah Ece Hiroshi Tateishi Ryoko Koga Mohamed O. Radwan Nefise Demir Mustafa Can Mutlu Dilsiz Aytemir Jun-ichiro Inoue Masami Otsuka Mikako Fujita Halilibrahim Ciftci Hasan DeMirci |
| author_sort | Omur Guven |
| collection | DOAJ |
| description | 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 “<i>Turkish DeLight</i>” 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. |
| first_indexed | 2024-03-09T16:32:00Z |
| format | Article |
| id | doaj.art-1202296dce524954b7f465f6ba2024b8 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T16:32:00Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-1202296dce524954b7f465f6ba2024b82023-11-24T15:00:32ZengMDPI AGPharmaceuticals1424-82472023-11-011611160810.3390/ph16111608Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New DerivativesOmur Guven0Belgin Sever1Faika Başoğlu-Ünal2Abdulilah Ece3Hiroshi Tateishi4Ryoko Koga5Mohamed O. Radwan6Nefise Demir7Mustafa Can8Mutlu Dilsiz Aytemir9Jun-ichiro Inoue10Masami Otsuka11Mikako Fujita12Halilibrahim Ciftci13Hasan DeMirci14Department of Molecular Biology and Genetics, Koç University, Istanbul 34450, TurkeyMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, European University of Lefke, Northern Cyprus, TR-10, Mersin 99770, TurkeyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul 34015, TurkeyMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Nanoscience and Nanotechnology, Izmir Katip Celebi University, Izmir 35620, TurkeyFaculty of Engineering and Architecture, Department of Engineering Sciences, Izmir Katip Celebi University, Izmir 35620, TurkeyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, İzmir Katip Çelebi University, Izmir 35620, TurkeyResearch Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Molecular Biology and Genetics, Koç University, Istanbul 34450, TurkeyDepartment of Molecular Biology and Genetics, Koç University, Istanbul 34450, TurkeyTumor 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 “<i>Turkish DeLight</i>” 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.https://www.mdpi.com/1424-8247/16/11/1608TRAF6zinc fingerRING domaincancerX-ray crystallographystructural biology |
| spellingShingle | Omur Guven Belgin Sever Faika Başoğlu-Ünal Abdulilah Ece Hiroshi Tateishi Ryoko Koga Mohamed O. Radwan Nefise Demir Mustafa Can Mutlu Dilsiz Aytemir Jun-ichiro Inoue Masami Otsuka Mikako Fujita Halilibrahim Ciftci Hasan DeMirci Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives Pharmaceuticals TRAF6 zinc finger RING domain cancer X-ray crystallography structural biology |
| title | Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives |
| title_full | Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives |
| title_fullStr | Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives |
| title_full_unstemmed | Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives |
| title_short | Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives |
| title_sort | structural characterization of traf6 n terminal for therapeutic uses and computational studies on new derivatives |
| topic | TRAF6 zinc finger RING domain cancer X-ray crystallography structural biology |
| url | https://www.mdpi.com/1424-8247/16/11/1608 |
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