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1.
Mol Cancer Ther ; 18(9): 1484-1496, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31285279

RESUMO

EYA proteins (EYA1-4) are critical developmental transcriptional cofactors that contain an EYA domain (ED) harboring Tyr phosphatase activity. EYA proteins are largely downregulated after embryogenesis but are reexpressed in cancers, and their Tyr phosphatase activity plays an important role in the DNA damage response and tumor progression. We previously identified a class of small-molecule allosteric inhibitors that specifically inhibit the Tyr phosphatase activity of EYA2. Herein, we determined the crystal structure of the EYA2 ED in complex with NCGC00249987 (a representative compound in this class), revealing that it binds to an induced pocket distant from the active site. NCGC00249987 binding leads to a conformational change of the active site that is unfavorable for Mg2+ binding, thereby inhibiting EYA2's Tyr phosphatase activity. We demonstrate, using genetic mutations, that migration, invadopodia formation, and invasion of lung adenocarcinoma cells are dependent on EYA2 Tyr phosphatase activity, whereas growth and survival are not. Further, we demonstrate that NCGC00249987 specifically targets migration, invadopodia formation, and invasion of lung cancer cells, but that it does not inhibit cell growth or survival. The compound has no effect on lung cancer cells carrying an EYA2 F290Y mutant that abolishes compound binding, indicating that NCGC00249987 is on target in lung cancer cells. These data suggest that the NCGC00249987 allosteric inhibitor can be used as a chemical probe to study the function of the EYA2 Tyr phosphatase activity in cells and may have the potential to be developed into an antimetastatic agent for cancers reliant on EYA2's Tyr phosphatase activity.

2.
Curr Med Chem ; 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31187703

RESUMO

Solution NMR spectroscopy plays important roles in understanding protein structures, dynamics and protein-protein/ligand interactions. In a target-based drug discovery project, NMR can serve an important function in the steps of hit identification and lead optimization. Fluorine is a valuable probe for evaluating protein conformational changes and protein-ligand interactions. Accumulated studies demonstrate that 19F-NMR will be playing important roles in fragment-based drug discovery (FBDD) and probing protein-ligand interactions. This review summarizes the application of 19F-NMR in understanding protein-ligand interactions and drug discovery. Several examples are included to show the roles of 19F-NMR in confirming identified hits/leads in the drug discovery process. In addition to identifying hits from fluorine-containing compound libraries, 19F-NMR will play an important role in drug discovery by providing a fast and robust way in novel hit identification. This technique can be used for ranking compounds with different binding affinities and particularly useful for screening competitive compounds when a reference ligand is available.

3.
Biomol NMR Assign ; 13(2): 327-332, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31175551

RESUMO

Bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) plays important roles in translation, making it an important target for the development of new antibacterial compounds. TrmD comprises two domains with the N-terminal domain binding to the S-adenosyl-L-methionine (SAM) cofactor and the C-terminal domain critical for tRNA binding. Bacterial TrmD is functional as a dimer. Here we report the backbone NMR resonance assignments for the full length TrmD protein of Pseudomonas aeruginosa. Most resonances were assigned and the secondary structure for each amino acid was determined according to the assigned backbone resonances. The availability of the assignment will be valuable for exploring molecular interactions of TrmD with ligands, inhibitors and tRNA.

4.
FEBS Lett ; 593(5): 554-561, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30742705

RESUMO

Syndecans are single-span membrane proteins playing important roles in cell-cell and cell-matrix interactions. The transmembrane domain of syndecans is critical for signal transduction across the cell membrane. Here, the structure of the transmembrane domain of syndecan-2 in detergent micelles was investigated using solution NMR spectroscopy. Backbone resonance assignment was obtained, and NMR studies show that the transmembrane domain forms a helix in detergent micelles, which is also supported by the hydrogen and deuterium exchange experiment. A study of the dynamics revealed the rigid structure of the transmembrane domain formed in solution, and paramagnetic relaxation enhancement defined the topology of the transmembrane domain in detergent micelles. This structural analysis may facilitate a better understanding of the role of the syndecan-2 transmembrane domain in signal transduction.

5.
Int J Mol Sci ; 20(1)2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30609728

RESUMO

In-cell nuclear magnetic resonance (NMR) is a method to provide the structural information of a target at an atomic level under physiological conditions and a full view of the conformational changes of a protein caused by ligand binding, post-translational modifications or protein⁻protein interactions in living cells. Previous in-cell NMR studies have focused on proteins that were overexpressed in bacterial cells and isotopically labeled proteins injected into oocytes of Xenopus laevis or delivered into human cells. Applications of in-cell NMR in probing protein modifications, conformational changes and ligand bindings have been carried out in mammalian cells by monitoring isotopically labeled proteins overexpressed in living cells. The available protocols and successful examples encourage wide applications of this technique in different fields such as drug discovery. Despite the challenges in this method, progress has been made in recent years. In this review, applications of in-cell NMR are summarized. The successful applications of this method in mammalian and bacterial cells make it feasible to play important roles in drug discovery, especially in the step of target engagement.


Assuntos
Descoberta de Drogas/métodos , Espectroscopia de Ressonância Magnética/métodos , Animais , Humanos , Ligação Proteica , Conformação Proteica
6.
Protein Expr Purif ; 154: 1-6, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30248452

RESUMO

The Zika virus (ZIKV) genome encodes a polyprotein that can be post-translationally processed into functional viral proteins. The viral protease is indispensable in the maturation of viral proteins. The Zika protease comprises of two components crucial for catalysis. The N-terminal region of NS3 contains the catalytic triad and approximately 40 amino acids of NS2B are essential for folding and protease activity. NS2B is a membrane protein with transmembrane domains that are critical for the localization of NS3 to the membrane. In this study, we expressed and purified full-length NS2B from ZIKV in E. coli. Purified NS2B was then reconstituted into lyso-myristoyl phosphatidylglycerol (LMPG) micelles. It was found that compared to wild type NS2B, NS2B C11S mutation in LMPG exhibited dispersed cross peaks in the 1H15N-HSQC spectrum, thereby suggesting the feasibility for structural characterization using solution NMR spectroscopy.

7.
Biomol NMR Assign ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30298375

RESUMO

Bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) is an important antibacterial target due to its essential role in translation. TrmD has two domains connected with a flexible linker. The N-terminal domain (NTD) of TrmD contains the S-adenosyl-L-methionine (SAM) cofactor binding site and the C-terminal domain is critical for tRNA binding. Here we report the backbone NMR resonance assignments for NTD of Pseudomonas aeruginosa TrmD. Its secondary structure was determined based on the assigned resonances. Relaxation analysis revealed that NTD existed as dimers in solution. NTD also exhibited thermal stability in solution. Its interactions with SAM and other compounds suggest it can be used for evaluating SAM competitive inhibitors by NMR.

8.
Biochem Biophys Res Commun ; 503(2): 691-696, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29908184

RESUMO

Zika virus (ZIKV) protease is a two-component complex in which NS3 contains the catalytic triad and NS2B cofactor region is important for protease folding and activity. A protease construct-eZiPro without the transmembrane domains of NS2B was designed. Structural study on eZiPro reveals that the Thr-Gly-Lys-Arg (TGKR) sequence at the C-terminus of NS2B binds to the active site after cleavage. The bZiPro construct only contains NS2B cofactor region and the N-terminus of NS3 without any artificial linker or protease cleavage site, giving rise to an empty pocket accessible to substrate and inhibitor binding. Herein, we demonstrate that the TGKR sequence of NS2B in eZiPro is dynamic. Peptides from NS2B with various lengths exhibit different binding affinities to bZiPro. TGKR binding to the active site in eZiPro does not affect protease binding to small-molecule compounds. Our results suggest that eZiPro will also be useful for evaluating small-molecule protease inhibitors.

9.
Biochim Biophys Acta Biomembr ; 1860(8): 1517-1527, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29758185

RESUMO

Linear antimicrobial peptides, with their rapid bactericidal mode of action, are well-suited for development as topical antibacterial drugs. We recently designed a synthetic linear 4-residue peptide, BRBR-NH2, with potent bactericidal activity against Staphylococcus aureus (MIC 6.25 µM), the main causative pathogen of human skin infections with an unknown mechanism of action. Herein, we describe a series of experiments conducted to gain further insights into its mechanism of action involving electron microscopy, artificial membrane dye leakage, solution- and solid-state NMR spectroscopy followed by molecular dynamics simulations. Experimental results point towards a SMART (Soft Membranes Adapt and Respond, also Transiently) mechanism of action, suggesting that the peptide can be developed as a topical antibacterial agent for treating drug-resistant Staphylococcus aureus infections.


Assuntos
Anti-Infecciosos/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Parede Celular/metabolismo , Sequência de Aminoácidos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Parede Celular/química , Lipossomos/química , Lipossomos/metabolismo , Espectroscopia de Ressonância Magnética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular
10.
Biochem J ; 475(12): 2043-2055, 2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29760238

RESUMO

The oncoprotein YAP (Yes-associated protein) requires the TEAD family of transcription factors for the up-regulation of genes important for cell proliferation. Disrupting YAP-TEAD interaction is an attractive strategy for cancer therapy. Targeting TEADs using small molecules that either bind to the YAP-binding pocket or the palmitate-binding pocket is proposed to disrupt the YAP-TEAD interaction. There is a need for methodologies to facilitate robust and reliable identification of compounds that occupy either YAP-binding pocket or palmitate-binding pocket. Here, using NMR spectroscopy, we validated compounds that bind to these pockets and also identify the residues in mouse TEAD4 (mTEAD4) that interact with these compounds. Flufenamic acid (FA) was used as a positive control for validation of palmitate-binding pocket-occupying compounds by NMR. Furthermore, we identify a hit from a fragment screen and show that it occupies a site close to YAP-binding pocket on the TEAD surface. Our results also indicate that purified mTEAD4 can catalyze autopalmitoylation. NMR studies on mTEAD4 revealed that exchanges exist in TEAD as NMR signal broadening was observed for residues close to the palmitoylation site. Mutating the palmitoylated cysteine (C360S mutant) abolished palmitoylation, while no significant changes in the NMR spectrum were observed for the mutant which still binds to YAP. We also show that FA inhibits TEAD autopalmitoylation. Our studies highlight the utility of NMR spectroscopy in identifying small molecules that bind to TEAD pockets and reinforce the notion that both palmitate-binding pocket and YAP-binding pocket are targetable.

11.
Structure ; 26(4): 555-564.e3, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29526431

RESUMO

Zika virus (ZIKV) infection has become a global public health concern. The viral NS2B-NS3 protease is an attractive antiviral target because of its role in maturation of viral non-structural proteins. Substrate-derived protease inhibitors have been investigated, but it remains challenging to develop them into drugs. Small-molecule inhibitors are of great interest in antiviral drug development. Here we report the structure and dynamics of ZIKV NS2B-NS3 protease covalently bound to a small-molecule inhibitor. Our crystallographic and NMR studies demonstrate that the inhibitor further stabilizes the closed conformation of ZIKV protease. Upon hydrolysis in situ into two fragments, the benzoyl group of the inhibitor forms a covalent bond with the side chain of catalytic residue S135, whereas the second fragment exhibits no obvious molecular interactions with the protease. This study provides a detailed mechanism of action for a covalent inhibitor, which will guide further development of ZIKV protease inhibitors.

12.
Biochim Biophys Acta Biomembr ; 1860(2): 442-450, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29055659

RESUMO

Dengue virus (DENV) non-structural (NS) 4A is a membrane protein essential for viral replication. The N-terminal region of NS4A contains several helices interacting with the cell membrane and the C-terminal region consists of three potential transmembrane regions. The secondary structure of the intact NS4A is not known as the previous structural studies were carried out on its fragments. In this study, we purified the full-length NS4A of DENV serotype 4 into dodecylphosphocholine (DPC) micelles. Solution NMR studies reveal that NS4A contains six helices in DPC micelles. The N-terminal three helices are amphipathic and interact with the membrane. The C-terminal three helices are embedded in micelles. Our results suggest that NS4A contains three transmembrane helices. Our studies provide for the first time structural information of the intact NS4A of DENV and will be useful for further understanding its role in viral replication.


Assuntos
Proteínas de Membrana/química , Micelas , Fosforilcolina/análogos & derivados , Estrutura Secundária de Proteína , Proteínas não Estruturais Virais/química , Sequência de Aminoácidos , Vírus da Dengue/genética , Vírus da Dengue/metabolismo , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Espectroscopia de Ressonância Magnética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Moleculares , Fosforilcolina/química , Fosforilcolina/metabolismo , Ligação Proteica , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
13.
Biomol NMR Assign ; 11(2): 225-229, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28808922

RESUMO

NSD3 is a histone H3 methyltransferase that plays an important role in chromatin biology. A construct containing the methyltransferase domain encompassing residues Q1049-K1299 of human NSD3 was obtained and biochemical activity was demonstrated using histone as a substrate. Here we report the backbone HN, N, Cα, C', and side chain Cß assignments of the construct in complex with S-adenosyl-L-methionine (SAM). Based on these assignments, secondary structures of NSD3/SAM complex in solution were determined.


Assuntos
Coenzimas/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Ressonância Magnética Nuclear Biomolecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Domínios PR-SET , Sequência de Aminoácidos , Humanos
14.
Trends Microbiol ; 25(10): 797-808, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28789826

RESUMO

The recent outbreak of Zika virus (ZIKV) infection has caused global concern due to its link to severe damage to the brain development of foetuses and neuronal complications in adult patients. A worldwide research effort has been undertaken to identify effective and safe treatment and vaccination options. Among the proposed viral and host components, the viral NS2B-NS3 protease represents an attractive drug target due to its essential role in the virus life cycle. Here, we outline recent progress in studies on the Zika protease. Biochemical, biophysical, and structural studies on different protease constructs provide new insight into the structure and activity of the protease. The unlinked construct displays higher enzymatic activity and better mimics the native state of the enzyme and therefore is better suited for drug discovery. Furthermore, the structure of the free enzyme adopts a closed conformation and a preformed active site. The availability of a lead fragment hit and peptide inhibitors, as well as the attainability of soakable crystals, suggest that the unlinked construct is a promising tool for drug discovery.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Peptídeo Hidrolases/metabolismo , Zika virus/efeitos dos fármacos , Zika virus/metabolismo , Animais , Descoberta de Drogas/métodos , Humanos , Conformação Proteica , Proteínas Virais/metabolismo
15.
Structure ; 25(8): 1242-1250.e3, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28689970

RESUMO

The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor, Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser135 of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease, respectively. Nuclear magnetic resonance studies demonstrate that the complex is in the closed conformation in solution. The chemical environment of residues surrounding the active site is sensitive to the bound inhibitor as demonstrated by the comparison with two other non-covalent dipeptides, Acyl-K-Agmatine (compound 2) and Acyl-KR-COOH (compound 3). Removing the aldehyde moiety in 1 converts the binding mode from a slow to a fast exchange regime. The structural dynamics information obtained in this study will guide future drug discovery against ZIKV and other flaviviruses.


Assuntos
Antivirais/farmacologia , Dipeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/química , Antivirais/química , Domínio Catalítico , Dipeptídeos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Ligação Proteica , RNA Helicases/química , RNA Helicases/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Zika virus/enzimologia
16.
FEBS Lett ; 591(15): 2338-2347, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28675775

RESUMO

The Zika virus (ZIKV) NS2B-NS3 protease is an important drug target. The conventional flaviviral protease constructs used for structural studies contain the NS2B cofactor region linked to the NS3 protease domain via a glycine-rich flexible linker. Here, we examined the structural dynamics of this conventional Zika protease (gZiPro) using NMR spectroscopy. Although the glycine-rich linker in gZiPro does not alter the overall folding of the protease in solution, gZiPro is not homogenous in ion exchange chromatography. Compared to the unlinked protease construct, the artificial linker affects the chemical environment of many residues including H51 in the catalytic triad. Our study provides a direct comparison of ZIKV protease constructs with and without an artificial linker.


Assuntos
Proteínas Recombinantes/química , Serina Endopeptidases/química , Proteínas Virais/química , Zika virus/enzimologia , Domínio Catalítico , Cromatografia por Troca Iônica , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Dobramento de Proteína , Proteínas Recombinantes/genética , Serina Endopeptidases/genética , Inibidores de Serino Proteinase/química , Proteínas Virais/genética
17.
Vitam Horm ; 105: 1-17, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28629512

RESUMO

Erythropoietin (EPO) is a hormone that is important for regulating red blood cell production. It is functional through binding to its receptor-EpoR. EpoR is a single-span membrane protein. It contains an extracellular region, a transmembrane domain, and a C-terminus. The extracellular region is important for binding to EPO, and its conformation is critical for signal transduction. The transmembrane domain contains 21 residues forming a helix which plays an important role in transferring ligand-induced conformational changes of the extracellular domain across the cell membrane. The C-terminal region contains the Janus kinase 2-binding sites and eight tyrosine residues that can be phosphorylated to become binding sites for transcription factors to active the downstream pathways. This chapter focuses on structural description of the domains of the EpoR. The recent progress in the structural determination of these domains is summarized, which will be useful for understanding their function in signal transduction.


Assuntos
Eritropoetina/metabolismo , Receptores da Eritropoetina/química , Receptores da Eritropoetina/metabolismo , Sequência de Aminoácidos , Animais , Humanos , Modelos Moleculares , Conformação Proteica , Domínios Proteicos , Receptores da Eritropoetina/genética
18.
Science ; 354(6319): 1597-1600, 2016 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-27940580

RESUMO

Zika virus (ZIKV) has rapidly emerged as a global public health concern. Viral NS2B-NS3 protease processes viral polyprotein and is essential for the virus replication, making it an attractive antiviral drug target. We report crystal structures at 1.58-angstrom resolution of the unlinked NS2B-NS3 protease from ZIKV as free enzyme and bound to a peptide reversely oriented at the active site. The unlinked NS2B-NS3 protease adopts a closed conformation in which NS2B engages NS3 to form an empty substrate-binding site. A second protease in the same crystal binds to the residues K14K15G16E17 from the neighboring NS3 in reverse orientation, resisting proteolysis. These features of ZIKV NS2B-NS3 protease may accelerate the discovery of structure-based antiviral drugs against ZIKV and related pathogenic flaviviruses.


Assuntos
Proteínas não Estruturais Virais/química , Zika virus/enzimologia , Domínio Catalítico , Cristalografia por Raios X , Oligopeptídeos/química , Ligação Proteica , Conformação Proteica , Proteólise , RNA Helicases/química , Serina Endopeptidases/química , Especificidade por Substrato
19.
Nat Commun ; 7: 13410, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845325

RESUMO

The recent outbreak of Zika virus (ZIKV) infections in the Americas represents a serious threat to the global public health. The viral protease that processes viral polyproteins during infection appears as an attractive drug target. Here we report a crystal structure at 1.84 Å resolution of ZIKV non-structural protein NS2B-NS3 protease with the last four amino acids of the NS2B cofactor bound at the NS3 active site. This structure represents a post-proteolysis state of the enzyme during viral polyprotein processing and provides insights into peptide substrate recognition by the protease. Nuclear magnetic resonance (NMR) studies and protease activity assays unravel the protein dynamics upon binding the protease inhibitor BPTI in solution and confirm this finding. The structural and functional insights of the ZIKV protease presented here should advance our current understanding of flavivirus replication and accelerate structure-based antiviral drug discovery against ZIKV.


Assuntos
Peptídeo Hidrolases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Zika virus/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Peptídeo Hidrolases/química , Ligação Proteica , Conformação Proteica , Proteólise , Proteínas não Estruturais Virais/química
20.
Sci Adv ; 2(9): e1501228, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27626070

RESUMO

The single-span membrane protein KCNE3 modulates a variety of voltage-gated ion channels in diverse biological contexts. In epithelial cells, KCNE3 regulates the function of the KCNQ1 potassium ion (K(+)) channel to enable K(+) recycling coupled to transepithelial chloride ion (Cl(-)) secretion, a physiologically critical cellular transport process in various organs and whose malfunction causes diseases, such as cystic fibrosis (CF), cholera, and pulmonary edema. Structural, computational, biochemical, and electrophysiological studies lead to an atomically explicit integrative structural model of the KCNE3-KCNQ1 complex that explains how KCNE3 induces the constitutive activation of KCNQ1 channel activity, a crucial component in K(+) recycling. Central to this mechanism are direct interactions of KCNE3 residues at both ends of its transmembrane domain with residues on the intra- and extracellular ends of the KCNQ1 voltage-sensing domain S4 helix. These interactions appear to stabilize the activated "up" state configuration of S4, a prerequisite for full opening of the KCNQ1 channel gate. In addition, the integrative structural model was used to guide electrophysiological studies that illuminate the molecular basis for how estrogen exacerbates CF lung disease in female patients, a phenomenon known as the "CF gender gap."


Assuntos
Fibrose Cística/metabolismo , Canal de Potássio KCNQ1/química , Complexos Multiproteicos/química , Canais de Potássio de Abertura Dependente da Tensão da Membrana/química , Animais , Canais de Cloreto/química , Biologia Computacional/métodos , Fibrose Cística/patologia , Fenômenos Eletrofisiológicos , Células Epiteliais/química , Células Epiteliais/metabolismo , Humanos , Canal de Potássio KCNQ1/metabolismo , Complexos Multiproteicos/metabolismo , Potássio/química , Potássio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Domínios Proteicos
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