ArticleProceedings of the National Academy of Sciences of the United States of America2014
Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
83 citing papers in PubMed, 139 citations in OpenAlex.
- Targeting Soluble Adenylyl Cyclase for On-Demand Contraception.Physiology (Bethesda, Md.) · 2026Review
- Structural insights enable drug discovery for the neuronal NBCn2 carbonate transporter.Nature communications · 2026Article
- Identification of Key Residues in Allosteric Signaling of Photoactivated Adenylyl Cyclase.bioRxiv : the preprint server for biology · 2026Article
- Soluble adenylyl cyclase in nonmammalian sperm is directly controlled by pH, not by HCOProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Sustained soluble adenylyl cyclase (sAC)-generated cAMP is necessary and sufficient for hyperactivated motility in human sperm.Human reproduction (Oxford, England) · 2026Article
- Primary Biliary Cholangitis Pathogenesis: A Pathophysiology-Based Narrative Review.International journal of molecular sciences · 2026Review
- Biochemical characterization of the full-length isoform of soluble adenylyl cyclase.The Journal of biological chemistry · 2025Article
- Sensing molecular carbon dioxide: a translational focus for respiratory disease.Physiological reviews · 2025Review
- Stomatal CO2 sensing in plants: control of gas exchange and interactions with environmental stimuli.Plant & cell physiology · 2025Review
- The Treatment of Primary Biliary Cholangitis: Time for Personalized Medicine.Clinical reviews in allergy & immunology · 2025Review
- Updating the Mechanism of Bicarbonate (HCOInternational journal of molecular sciences · 2025Article
- Bovine serum albumin-induced calcium influx triggers soluble adenylyl cyclase activation and cyclic AMP signalling pathways in mouse sperm capacitation.The Journal of physiology · 2025Article
- Obesity-driven oleoylcarnitine accumulation in tumor microenvironment promotes breast cancer metastasis-like phenotype.Acta pharmaceutica Sinica. B · 2025Article
- Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice.eLife · 2025Article
- Cyclic AMP Rescue of Motility in Sperm Devoid of Soluble Adenylyl Cyclase.International journal of molecular sciences · 2025Article
- Repeated-Dose Toxicity of Lauric Acid and Its Preventive Effect Against Tracheal Hyper-Responsiveness in Wistar Rats with PossiblePharmaceuticals (Basel, Switzerland) · 2025Article
- Molecular Mechanisms of Fibrosis in Cholestatic Liver Diseases and Regenerative Medicine-Based Therapies.Cells · 2024Review
- David Garbers and the Birth of cAMP Biology in Mammalian Sperm.Molecular reproduction and development · 2024Review
- The role of soluble adenylyl cyclase in sensing and regulating intracellular pH.Pflugers Archiv : European journal of physiology · 2024Review
- A Non-Functional Carbon Dioxide-Mediated Post-Translational Modification on Nucleoside Diphosphate Kinase ofInternational journal of molecular sciences · 2024Article
23 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
cAMP is an evolutionary conserved, prototypic second messenger regulating numerous cellular functions. In mammals, cAMP is synthesized by one of 10 homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3(-)); it thereby serves as a cellular sensor for HCO3(-), carbon dioxide (CO2), and pH in physiological functions, such as sperm activation, aqueous humor formation, and metabolic regulation. Here, we describe crystal structures of human sAC catalytic domains in the apo state and in complex with substrate analog, products, and regulators. The activator HCO3(-) binds adjacent to Arg176, which acts as a switch that enables formation of the catalytic cation sites. An anionic inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, inhibits sAC through binding to the active site entrance, which blocks HCO3(-) activation through steric hindrance and trapping of the Arg176 side chain. Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3(-) sensing and a basis for targeting this system with drugs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.