Structure-based characterization of novel TRPV5 inhibitors.

Abstract:

: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.

journal_name

Elife

journal_title

eLife

authors

Hughes TE,Del Rosario JS,Kapoor A,Yazici AT,Yudin Y,Fluck EC 3rd,Filizola M,Rohacs T,Moiseenkova-Bell VY

doi

10.7554/eLife.49572

subject

Has Abstract

pub_date

2019-10-25 00:00:00

issn

2050-084X

pii

49572

journal_volume

8

pub_type

杂志文章

相关文献

eLife文献大全
  • tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish.

    abstract::The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.37202

    authors: Ignatius MS,Hayes MN,Moore FE,Tang Q,Garcia SP,Blackburn PR,Baxi K,Wang L,Jin A,Ramakrishnan A,Reeder S,Chen Y,Nielsen GP,Chen EY,Hasserjian RP,Tirode F,Ekker SC,Langenau DM

    更新日期:2018-09-07 00:00:00

  • Sensorimotor pathway controlling stopping behavior during chemotaxis in the Drosophila melanogaster larva.

    abstract::Sensory navigation results from coordinated transitions between distinct behavioral programs. During chemotaxis in the Drosophila melanogaster larva, the detection of positive odor gradients extends runs while negative gradients promote stops and turns. This algorithm represents a foundation for the control of sensory...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.38740

    authors: Tastekin I,Khandelwal A,Tadres D,Fessner ND,Truman JW,Zlatic M,Cardona A,Louis M

    更新日期:2018-11-22 00:00:00

  • Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense.

    abstract::Macrophage-mediated phagocytosis and cytokine production represent the front lines of resistance to bacterial invaders. A key feature of this pro-inflammatory response in mammals is the complex remodeling of cellular metabolism towards aerobic glycolysis. Although the function of bactericidal macrophages is highly con...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.50414

    authors: Krejčová G,Danielová A,Nedbalová P,Kazek M,Strych L,Chawla G,Tennessen JM,Lieskovská J,Jindra M,Doležal T,Bajgar A

    更新日期:2019-10-14 00:00:00

  • Cryo-EM structure of VASH1-SVBP bound to microtubules.

    abstract::The dynamic tyrosination-detyrosination cycle of α-tubulin regulates microtubule functions. Perturbation of this cycle impairs mitosis, neural physiology, and cardiomyocyte contraction. The carboxypeptidases vasohibins 1 and 2 (VASH1 and VASH2), in complex with the small vasohibin-binding protein (SVBP), mediate α-tub...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.58157

    authors: Li F,Li Y,Ye X,Gao H,Shi Z,Luo X,Rice LM,Yu H

    更新日期:2020-08-10 00:00:00

  • Step-to-step variations in human running reveal how humans run without falling.

    abstract::Humans can run without falling down, usually despite uneven terrain or occasional pushes. Even without such external perturbations, intrinsic sources like sensorimotor noise perturb the running motion incessantly, making each step variable. Here, using simple and generalizable models, we show that even such small step...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.38371

    authors: Seethapathi N,Srinivasan M

    更新日期:2019-03-19 00:00:00

  • The perils of cheating.

    abstract::Experiments on mitochondrial DNA in worms highlight that cheating does not always pay off. ...

    journal_title:eLife

    pub_type: 评论,杂志文章

    doi:10.7554/eLife.62222

    authors: Camus MF

    更新日期:2020-09-22 00:00:00

  • Division of labor in bacteria.

    abstract::The emergence of subpopulations that perform distinct metabolic roles has been observed in populations of genetically identical bacteria. ...

    journal_title:eLife

    pub_type: 评论,杂志文章

    doi:10.7554/eLife.38578

    authors: Dal Co A,Brannon C,Ackermann M

    更新日期:2018-06-29 00:00:00

  • The synaptic ribbon is critical for sound encoding at high rates and with temporal precision.

    abstract::We studied the role of the synaptic ribbon for sound encoding at the synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron and immunofluorescence microscopy revealed a lack of synaptic ribbons and an assembly of several small active zones (AZs) at each ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.29275

    authors: Jean P,Lopez de la Morena D,Michanski S,Jaime Tobón LM,Chakrabarti R,Picher MM,Neef J,Jung S,Gültas M,Maxeiner S,Neef A,Wichmann C,Strenzke N,Grabner C,Moser T

    更新日期:2018-01-12 00:00:00

  • Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation.

    abstract::T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.08698

    authors: Ramiscal RR,Parish IA,Lee-Young RS,Babon JJ,Blagih J,Pratama A,Martin J,Hawley N,Cappello JY,Nieto PF,Ellyard JI,Kershaw NJ,Sweet RA,Goodnow CC,Jones RG,Febbraio MA,Vinuesa CG,Athanasopoulos V

    更新日期:2015-10-23 00:00:00

  • AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR-CHK2 interaction and prostate cancer survival.

    abstract::We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2 and ionizing radiation (IR) increases this int...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.51378

    authors: Ta HQ,Dworak N,Ivey ML,Roller DG,Gioeli D

    更新日期:2020-06-24 00:00:00

  • Dynamic control of hippocampal spatial coding resolution by local visual cues.

    abstract::The ability to flexibly navigate an environment relies on a hippocampal-dependent cognitive map. External space can be internally mapped at different spatial resolutions. However, whether hippocampal spatial coding resolution can rapidly adapt to local features of an environment remains unclear. To explore this possib...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.44487

    authors: Bourboulou R,Marti G,Michon FX,El Feghaly E,Nouguier M,Robbe D,Koenig J,Epsztein J

    更新日期:2019-03-01 00:00:00

  • Discovering and deciphering relationships across disparate data modalities.

    abstract::Understanding the relationships between different properties of data, such as whether a genome or connectome has information about disease status, is increasingly important. While existing approaches can test whether two properties are related, they may require unfeasibly large sample sizes and often are not interpret...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.41690

    authors: Vogelstein JT,Bridgeford EW,Wang Q,Priebe CE,Maggioni M,Shen C

    更新日期:2019-01-15 00:00:00

  • Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone.

    abstract::We report the crystal structure of nuclear import receptor Importin-9 bound to its cargo, the histones H2A-H2B. Importin-9 wraps around the core, globular region of H2A-H2B to form an extensive interface. The nature of this interface coupled with quantitative analysis of deletion mutants of H2A-H2B suggests that the N...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.43630

    authors: Padavannil A,Sarkar P,Kim SJ,Cagatay T,Jiou J,Brautigam CA,Tomchick DR,Sali A,D'Arcy S,Chook YM

    更新日期:2019-03-11 00:00:00

  • Cryo-EM visualization of the ribosome in termination complex with apo-RF3 and RF1.

    abstract::Termination of messenger RNA translation in Bacteria and Archaea is initiated by release factors (RFs) 1 or 2 recognizing a stop codon in the ribosomal A site and releasing the peptide from the P-site transfer RNA. After release, RF-dissociation is facilitated by the G-protein RF3. Structures of ribosomal complexes wi...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.00411

    authors: Pallesen J,Hashem Y,Korkmaz G,Koripella RK,Huang C,Ehrenberg M,Sanyal S,Frank J

    更新日期:2013-06-04 00:00:00

  • Palaeogenomes of Eurasian straight-tusked elephants challenge the current view of elephant evolution.

    abstract::The straight-tusked elephants Palaeoloxodon spp. were widespread across Eurasia during the Pleistocene. Phylogenetic reconstructions using morphological traits have grouped them with Asian elephants (Elephas maximus), and many paleontologists place Palaeoloxodon within Elephas. Here, we report the recovery of full mit...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.25413

    authors: Meyer M,Palkopoulou E,Baleka S,Stiller M,Penkman KEH,Alt KW,Ishida Y,Mania D,Mallick S,Meijer T,Meller H,Nagel S,Nickel B,Ostritz S,Rohland N,Schauer K,Schüler T,Roca AL,Reich D,Shapiro B,Hofreiter M

    更新日期:2017-06-06 00:00:00

  • Control of endothelial cell polarity and sprouting angiogenesis by non-centrosomal microtubules.

    abstract::Microtubules control different aspects of cell polarization. In cells with a radial microtubule system, a pivotal role in setting up asymmetry is attributed to the relative positioning of the centrosome and the nucleus. Here, we show that centrosome loss had no effect on the ability of endothelial cells to polarize an...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.33864

    authors: Martin M,Veloso A,Wu J,Katrukha EA,Akhmanova A

    更新日期:2018-03-16 00:00:00

  • Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha.

    abstract::The neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA localization. Pur-alpha-deficient mice die after birth with pleiotropic neuronal defects. Here, we report the crystal structure of the DNA-/RNA-binding domain of Pur-alpha in complex with ssDNA. It reveals base-specif...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.11297

    authors: Weber J,Bao H,Hartlmüller C,Wang Z,Windhager A,Janowski R,Madl T,Jin P,Niessing D

    更新日期:2016-01-08 00:00:00

  • Sorting of a multi-subunit ubiquitin ligase complex in the endolysosome system.

    abstract::The yeast Dsc E3 ligase complex has long been recognized as a Golgi-specific protein ubquitination system. It shares a striking sequence similarity to the Hrd1 complex that plays critical roles in the ER-associated degradation pathway. Using biochemical purification and mass spectrometry, we identified two novel Dsc s...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.33116

    authors: Yang X,Arines FM,Zhang W,Li M

    更新日期:2018-01-22 00:00:00

  • Rhythmic coordination of hippocampal neurons during associative memory processing.

    abstract::Hippocampal oscillations are dynamic, with unique oscillatory frequencies present during different behavioral states. To examine the extent to which these oscillations reflect neuron engagement in distinct local circuit processes that are important for memory, we recorded single cell and local field potential activity...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.09849

    authors: Rangel LM,Rueckemann JW,Riviere PD,Keefe KR,Porter BS,Heimbuch IS,Budlong CH,Eichenbaum H

    更新日期:2016-01-11 00:00:00

  • Competency-based assessment for the training of PhD students and early-career scientists.

    abstract::The training of PhD students and early-career scientists is largely an apprenticeship in which the trainee associates with an expert to become an independent scientist. But when is a PhD student ready to graduate, a postdoctoral scholar ready for an independent position, or an early-career scientist ready for advanced...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.34801

    authors: Verderame MF,Freedman VH,Kozlowski LM,McCormack WT

    更新日期:2018-05-31 00:00:00

  • Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages.

    abstract::How Mycobacterium tuberculosis (Mtb) rewires macrophage energy metabolism to facilitate survival is poorly characterized. Here, we used extracellular flux analysis to simultaneously measure the rates of glycolysis and respiration in real time. Mtb infection induced a quiescent energy phenotype in human monocyte-derive...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.39169

    authors: Cumming BM,Addicott KW,Adamson JH,Steyn AJ

    更新日期:2018-11-16 00:00:00

  • KATANIN-dependent mechanical properties of the stigmatic cell wall mediate the pollen tube path in Arabidopsis.

    abstract::Successful fertilization in angiosperms depends on the proper trajectory of pollen tubes through the pistil tissues to reach the ovules. Pollen tubes first grow within the cell wall of the papilla cells, applying pressure to the cell. Mechanical forces are known to play a major role in plant cell shape by controlling ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.57282

    authors: Riglet L,Rozier F,Kodera C,Bovio S,Sechet J,Fobis-Loisy I,Gaude T

    更新日期:2020-09-01 00:00:00

  • Gap junction networks in mushroom bodies participate in visual learning and memory in Drosophila.

    abstract::Gap junctions are widely distributed in the brains across species and play essential roles in neural information processing. However, the role of gap junctions in insect cognition remains poorly understood. Using a flight simulator paradigm and genetic tools, we found that gap junctions are present in Drosophila Kenyo...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.13238

    authors: Liu Q,Yang X,Tian J,Gao Z,Wang M,Li Y,Guo A

    更新日期:2016-05-24 00:00:00

  • Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium.

    abstract::D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, th...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.09358

    authors: Gantz SC,Robinson BG,Buck DC,Bunzow JR,Neve RL,Williams JT,Neve KA

    更新日期:2015-08-26 00:00:00

  • Behavioural diversity of bonobo prey preference as a potential cultural trait.

    abstract::The importance of cultural processes to behavioural diversity in our closest living relatives is central to revealing the evolutionary origins of human culture. However, the bonobo is often overlooked as a candidate model. Further, a prominent critique to many examples of proposed animal cultures is premature exclusio...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.59191

    authors: Samuni L,Wegdell F,Surbeck M

    更新日期:2020-09-01 00:00:00

  • A conserved function for pericentromeric satellite DNA.

    abstract::A universal and unquestioned characteristic of eukaryotic cells is that the genome is divided into multiple chromosomes and encapsulated in a single nucleus. However, the underlying mechanism to ensure such a configuration is unknown. Here, we provide evidence that pericentromeric satellite DNA, which is often regarde...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.34122

    authors: Jagannathan M,Cummings R,Yamashita YM

    更新日期:2018-03-26 00:00:00

  • Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator.

    abstract::MarR (multiple antibiotic resistance repressor) family proteins are bacterial repressors that regulate transcription in response to a wide range of chemical signals. Although specific features of MarR family function have been described, the role of atomic motions in MarRs remains unexplored thus limiting insights int...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.37268

    authors: Capdevila DA,Huerta F,Edmonds KA,Le MT,Wu H,Giedroc DP

    更新日期:2018-10-17 00:00:00

  • Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor.

    abstract::Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.30688

    authors: Li J,White JT,Saavedra H,Wrabl JO,Motlagh HN,Liu K,Sowers J,Schroer TA,Thompson EB,Hilser VJ

    更新日期:2017-10-12 00:00:00

  • Notochord vacuoles absorb compressive bone growth during zebrafish spine formation.

    abstract::The vertebral column or spine assembles around the notochord rod which contains a core made of large vacuolated cells. Each vacuolated cell possesses a single fluid-filled vacuole, and loss or fragmentation of these vacuoles in zebrafish leads to spine kinking. Here, we identified a mutation in the kinase gene dstyk tha...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.51221

    authors: Bagwell J,Norman J,Ellis K,Peskin B,Hwang J,Ge X,Nguyen SV,McMenamin SK,Stainier DY,Bagnat M

    更新日期:2020-01-29 00:00:00

  • Structural basis of TRPC4 regulation by calmodulin and pharmacological agents.

    abstract::Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin (CaM). Molecular details of both CaM and drug bi...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.60603

    authors: Vinayagam D,Quentin D,Yu-Strzelczyk J,Sitsel O,Merino F,Stabrin M,Hofnagel O,Yu M,Ledeboer MW,Nagel G,Malojcic G,Raunser S

    更新日期:2020-11-25 00:00:00