دورية أكاديمية
أعرض في EDS

Structure-based characterization of novel TRPV5 inhibitors.

التفاصيل البيبلوغرافية
العنوان: Structure-based characterization of novel TRPV5 inhibitors.
المؤلفون: Hughes TE; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States., Del Rosario JS; Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States., Kapoor A; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States., Yazici AT; Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States., Yudin Y; Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States., Fluck EC 3rd; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States., Filizola M; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States., Rohacs T; Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States., Moiseenkova-Bell VY; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
المصدر: ELife [Elife] 2019 Oct 25; Vol. 8. Date of Electronic Publication: 2019 Oct 25.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Enzyme Inhibitors/*chemical synthesis , Enzyme Inhibitors/*pharmacology , TRPV Cation Channels/*antagonists & inhibitors , TRPV Cation Channels/*chemistry, Binding Sites ; Cryoelectron Microscopy ; HEK293 Cells ; Humans ; Molecular Docking Simulation ; Protein Conformation
مستخلص: Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we performed structure-based virtual screening (SBVS) at a previously identified TRPV5 inhibitor binding site coupled with electrophysiology screening and identified three novel inhibitors of TRPV5, one of which exhibits high affinity, and specificity for TRPV5 over other TRP channels, including its close homologue TRPV6. Cryo-electron microscopy of TRPV5 in the presence of the specific inhibitor and its parent compound revealed novel binding sites for this channel. Structural and functional analysis have allowed us to suggest a mechanism of action for the selective inhibition of TRPV5 and lay the groundwork for rational design of new classes of TRPV5 modulators.
Competing Interests: TH, JD, AK, AY, YY, EF, MF, TR, VM No competing interests declared
(© 2019, Hughes et al.)
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معلومات مُعتمدة: R01GM131048 United States GM NIGMS NIH HHS; R01GM093290 United States GM NIGMS NIH HHS; R01 GM129357 United States GM NIGMS NIH HHS; R01GM103899 United States GM NIGMS NIH HHS; R01GM129357 United States GM NIGMS NIH HHS; S10 OD018522 United States OD NIH HHS; T32 GM132039 United States GM NIGMS NIH HHS; MCB080077 International National Science Foundation; R01 NS055159 United States NS NINDS NIH HHS; ACI-1053575 International National Science Foundation; R01NSNS055159 United States NS NINDS NIH HHS; R01 GM103899 United States GM NIGMS NIH HHS; R01 GM093290 United States GM NIGMS NIH HHS; R01 GM131048 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: Cryo-EM; S. cerevisiae; TRP channel; TRPV5; inhibitors; ion channal; molecular biophysics; structural biology; structure-based virtual screening
سلسلة جزيئية: PDB 6PBF; 6PBE
المشرفين على المادة: 0 (Enzyme Inhibitors)
0 (TRPV Cation Channels)
0 (TRPV5 protein, human)
تواريخ الأحداث: Date Created: 20191025 Date Completed: 20200312 Latest Revision: 20201110
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6834369
DOI: 10.7554/eLife.49572
PMID: 31647410
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.49572