4CLK
Crystal structure of human soluble Adenylyl Cyclase in complex with alpha,beta-methyleneadenosine-5'-triphosphate
Summary for 4CLK
| Entry DOI | 10.2210/pdb4clk/pdb |
| Related | 4CLF 4CLL 4CLP 4CLS 4CLT 4CLU 4CLW 4CLY 4CLZ 4CM0 4CM2 |
| Descriptor | ADENYLATE CYCLASE TYPE 10, DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, CHLORIDE ION, ... (7 entities in total) |
| Functional Keywords | lyase, adenosine-3'\, 5'-cyclic-monophosphate, adenosine-5'-triphosphate |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 55158.73 |
| Authors | Kleinboelting, S.,Weyand, M.,Steegborn, C. (deposition date: 2014-01-15, release date: 2014-03-05, Last modification date: 2024-11-13) |
| Primary citation | Kleinboelting, S.,Diaz, A.,Moniot, S.,Van Den Heuvel, J.,Weyand, M.,Levin, L.R.,Buck, J.,Steegborn, C. Crystal Structures of Human Soluble Adenylyl Cyclase Reveal Mechanisms of Catalysis and of its Activation Through Bicarbonate. Proc.Natl.Acad.Sci.USA, 111:3727-, 2014 Cited by PubMed 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. PubMed: 24567411DOI: 10.1073/PNAS.1322778111 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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