5d0r

Crystal structure of human soluble Adenylyl Cyclase with the inhibitor bithionol

spinqualitylabelsall models 5d0r, resolution 2.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5d0r is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.24Å Ligands: ACT, B1T, CME, DMS, EDO, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ADCYA_HUMAN Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry. Function ADCYA_HUMAN Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation. Publication Abstract from PubMed The signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (ACs) and one soluble AC (sAC). Despite similarities in their catalytic domains, these ACs differ in regulation. Transmembrane ACs respond to G proteins, whereas sAC is uniquely activated by bicarbonate. Via bicarbonate regulation, sAC acts as a physiological sensor for pH/bicarbonate/CO2, and it has been implicated as a therapeutic target, e.g. for diabetes, glaucoma, and a male contraceptive. Here we identify the bisphenols bithionol and hexachlorophene as potent, sAC-specific inhibitors. Inhibition appears mostly non-competitive with the substrate ATP, indicating that they act via an allosteric site. To analyze the interaction details, we solved a crystal structure of an sAC.bithionol complex. The structure reveals that the compounds are selective for sAC because they bind to the sAC-specific, allosteric binding site for the physiological activator bicarbonate. Structural comparison of the bithionol complex with apo-sAC and other sAC.ligand complexes along with mutagenesis experiments reveals an allosteric mechanism of inhibition; the compound induces rearrangements of substrate binding residues and of Arg(176), a trigger between the active site and allosteric site. Our results thus provide 1) novel insights into the communication between allosteric regulatory and active sites, 2) a novel mechanism for sAC inhibition, and 3) pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. These studies provide support for the future development of sAC-modulating drugs. Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site.,Kleinboelting S, Ramos-Espiritu L, Buck H, Colis L, van den Heuvel J, Glickman JF, Levin LR, Buck J, Steegborn C J Biol Chem. 2016 Apr 29;291(18):9776-84. doi: 10.1074/jbc.M115.708255. Epub 2016, Mar 9. PMID:26961873 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 3D Adenylyl cyclase 3D structures

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