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AMP-activated kinase (AMPK) is central to sensing energy status in eukaryotic cells via binding of AMP and ATP to CBS (cystathionine beta-synthase) domains in the regulatory gamma subunit. The structure of a CBS-domain pair from human AMPK gamma1 in complex with the physiological activator AMP and the pharmacological activator ZMP (AICAR) is presented.
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http://dx.doi.org/10.1107/S0907444907009110 | DOI Listing |
Mol Biotechnol
July 2025
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, 1417614335, Iran.
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step of GTP biosynthesis. The multilevel regulation of the enzyme complicates its inhibition to treat diseases such as retinitis pigmentosa (RP) where modulation of the isozyme IMPDH1 is disrupted by mutations in a GTP-binding site on its regulatory CBS domain. Here, we hypothesize that upsetting the ATP-binding site 1 on the CBS domain, which contributes to all levels of the enzyme regulation, can endow it with the conformational features characteristic of the inhibited form of IMPDH1.
View Article and Find Full Text PDFInt J Mol Sci
February 2025
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Magnesium, the most abundant divalent metal within the cell, is essential for physiological function and critical in cellular signaling. To maintain cellular homeostasis, intracellular magnesium levels are tightly regulated, as dysregulation is linked to numerous diseases, including cancer, diabetes, cardiovascular disorders, and neurological conditions. Over the past two decades, extensive research on magnesium-regulating proteins has provided valuable insight into their pathogenic and therapeutic potential.
View Article and Find Full Text PDFJ Physiol
March 2025
Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes, Disease and Therapy Program, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
CLC channels and transporters have large C-terminal regions which contain two cystathionine β-synthetase (CBS) domains. It has been hypothesized that conformational changes in these domains upon nucleotide binding modulate the gating of the CLC dimer. It is not clear how rearrangements that occur in the CBS domains are transmitted to the ion pathway, as CBS domains interact with the rest of the channel at multiple locations and some of these sites are not visible in recent solved cryogenic electron microscopy structures or are difficult to model using the AlphaFold server.
View Article and Find Full Text PDFInt J Mol Sci
May 2024
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119899, Russia.
Regulatory cystathionine β-synthase (CBS) domains are widespread in proteins; however, difficulty in structure determination prevents a comprehensive understanding of the underlying regulation mechanism. Tetrameric microbial inorganic pyrophosphatase containing such domains (CBS-PPase) is allosterically inhibited by AMP and ADP and activated by ATP and cell alarmones diadenosine polyphosphates. Each CBS-PPase subunit contains a pair of CBS domains but binds cooperatively to only one molecule of the mono-adenosine derivatives.
View Article and Find Full Text PDFInt J Mol Sci
December 2023
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.
Regulatory adenine nucleotide-binding cystathionine β-synthase (CBS) domains are widespread in proteins; however, information on the mechanism of their modulating effects on protein function is scarce. The difficulty in obtaining structural data for such proteins is ascribed to their unusual flexibility and propensity to form higher-order oligomeric structures. In this study, we deleted the most movable domain from the catalytic part of a CBS domain-containing bacterial inorganic pyrophosphatase (CBS-PPase) and characterized the deletion variant both structurally and functionally.
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