Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most frequent mutation is the deletion of F508 in the first nucleotide binding fold (NBF1). It induces a perturbation in the folding of NBF1, which impedes posttranslational maturation of CFTR. Determination of the three-dimensional structure of NBF1 would help to understand this defect. We present a novel model for NBF1 built from the crystal structure of bovine mitochondrial F1-ATPase protein. This model gives a reasonable interpretation of the effect of mutations on the maturation of the protein and, in agreement with the CD data, leads to reconsideration of the limits of NBF1 within CFTR.
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PMID:A novel model for the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator. 917 73

Cystic fibrosis is a human monogenic genetic disease caused by mutations in the cystic fibrosis (CF) gene, which encodes a membrane protein which functions as a channel: the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most frequent mutation, a deletion of phenylalanine F508 (delta F508), is located in the first nucleotide binding domain of CFTR: NBF1. This mutation leads to a folding defect in NBF1, responsible for an incomplete maturation of CFTR. The absence of CFTR at the surface of epithelial cells causes the disease. Determination of the three-dimensional (3D) structure of NBF1 is a key step to understanding the alterations induced by the mutation. In the absence of any experimental data, we have chosen to build a 3D model for NBF1. This model was built by homology modelling starting from F1-ATPase, the only protein of known 3D structure in the ATP binding cassette (ABC) family. This new model defines the central and critical position of F508, predicted in the hydrophobic core of NBF1. F508 indeed could be involved in hydrophobic interactions to ensure a correct folding pathway. Moreover, this model enables the localization of the LSGGQ sequence (a highly conserved sequence in the ABC family) in a loop, at the surface of the protein. This reinforces the hypothesis of its role for mediation of domain-domain interactions of functional significance for the channel regulation. Finally, the model also allows redefinition of the ends of NBF1 within the CFTR sequence. These extremities are defined by the secondary structure elements that are involved in the NBF1 fold. They lead to reconsideration of the C-terminal limit which was initially defined by the end of exon 12.
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PMID:Insight into cystic fibrosis by structural modelling of CFTR first nucleotide binding fold (NBF1). 918 Nov 19

Members of the ABC transporter superfamily contain two nucleotide binding domains. To date, the three dimensional structure of no member of this super-family has been elucidated. To gain structural insight, the known structures of several other nucleotides binding proteins can be used as a framework for modeling these domains. We have modeled both nucleotide binding domains of the protein CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) using the two similar domains of mitochondrial F1-ATPase. The models obtained, provide useful insights into the putative functions of these domains and their possible interaction as well as a rationale for the basis of Cystic Fibrosis causing mutations. First, the two nucleotide binding domains (folds) of CFTR are each predicted to span a 240-250 amino acid sequence rather than the 150-160 amino acid sequence originally proposed. Second, the first nucleotide binding fold, is predicted to catalyze significant rates of ATP hydrolysis as a catalytic base (E504) resides near the y phosphate of ATP. This prediction has been verified experimentally [Ko, Y.H., and Pedersen, P.L. (1995) J. Biol. Chem. 268, 24330-24338], providing support for the model. In contrast, the second nucleotide binding fold is predicted at best to be a weak ATPase as the glutamic acid residue is replaced with a glutamine. Third, F508, which when deleted causes approximately 70% of all cases of cystic fibrosis, is predicted to lie in a cleft near the nucleotide binding pocket. All other disease causing mutations within the two nucleotide binding domains of CFTR either reside near the Walker A and Walker B consensus motifs in the heart of the nucleotide binding pocket, or in the C motif which lies outside but near the nucleotide binding pocket. Finally, the two nucleotide binding domains of CFTR are predicted to interact, and in one of the two predicted orientations, F508 resides near the interface. This is the first report where both nucleotide binding domains of an ABC transporter and their putative domain-domain interactions have been modeled in three dimensions. The methods and the template used in this work can be used to analyze the structures and function of the nucleotide binding domains of all other members of the ABC transporter super-family.
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PMID:Modeling of nucleotide binding domains of ABC transporter proteins based on a F1-ATPase/recA topology: structural model of the nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator (CFTR). 951 35

Today we know there are four different types of ATPases that operate within biological membranes with the purpose of moving many different types of ions or molecules across these membranes. Some of these ions or molecules are transported into cells, some out of cells, and some in or out of organelles within cells. These ATPases span the biological world from bacteria to eukaryotic cells and have become most simply and commonly known as "transport ATPases." The price that each cell type pays for transport work is counted in molecules of hydrolyzed ATP, a metabolic currency that is itself regenerated by a transport ATPase working in reverse, i.e., the ATP synthase. Four major classes of transport ATPases, the P, V, F, and ABC types are now known. In addition to being involved in many different types of biological/physiological processes, mutations in these proteins also account for a large number of diseases. The purpose of this introductory article to a mini-review series on transport ATPases is to provide the reader with a very brief and focused look at this important area of research that has an interesting history and bears significance to cell physiology, biochemistry, immunology, nanotechnology, and medicine, including drug discovery. The latter involves potential applications to a whole host of diseases ranging from cancer to those that affect bones (osteoporosis), ears (hearing), eyes (macromolecular degeneration), the heart (hypercholesterolemia/cardiac arrest,), immune system (immune deficiency disease), kidney (nephrotoxicity), lungs (cystic fibrosis), pancreas (diabetes and cystic fibrosis), skin (Darier disease), and stomach (ulcers).
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PMID:Transport ATPases: structure, motors, mechanism and medicine: a brief overview. 1669 64

Transport ATPases can be lumped into four distinct types, P, F, V, and ABC, with the first three designated 20 years ago (Pedersen, P.L. and Carafoli, E., Trends Biochem. Sci. 12, 146-150, 1987) and the ABC type included more recently. The mini-reviews (>20) that comprise this volume of the Journal of Bioenergetics and Biomembranes describe work presented at the 2007 FASEB Conference (6th) on Transport ATPases (Kathleen Sweadner, Chair; Rajini Rao, Co-Chair). Since these conferences began in 1997, the "transport ATPase field" has seen tremendous progress. Advances include a much better understanding of the structure, mechanism, and regulation of each of the four major ATPase types as well as their physiological and medical relevance. In fact, the transport ATPase field has entered a new era in which work on these enzymes is likely to contribute to new therapies for multiple diseases that affect both people and animals. Among these are cancer and heart disease, mitochondrial diseases, osteoporosis, macromolecular degeneration, immune deficiency, cystic fibrosis, diabetes, ulcers, nephro-toxicity, hearing loss, skin disorders, lupus, and malaria. In addition, as several members of the transport ATPase family include those involved in drug resistance their study may help alleviate this recurring problem in drug development. Finally, the transport ATPase field is also paving the way for nanotechnology focused on nano-motors with work on the F-type ATPases (F(0)F(1)) leading the way. These ATPases driven in reverse by a proton gradient have the capacity to interconvert electrochemical energy into mechanical energy and finally into chemical energy conserved in the terminal bond of ATP. In mammalian mitochondria these events occur on a larger complex or "nano-machine" called the "ATP synthasome" that consists of the ATP synthase in complex formation with carriers for P(i) and ADP/ATP.
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PMID:Transport ATPases into the year 2008: a brief overview related to types, structures, functions and roles in health and disease. 1817 9

Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in M. abscessusin vitro, consistent with the drug targeting the F_oF₁ ATP synthase. Importantly, despite a failure to select in vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus Overall, this study indicates that BDQ is active against M. abscessusin vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections.
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PMID:Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish. 2880 17

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