Adenylyl cyclase Structure

Hanoune, J., Y. Pouille, E. Tzavara, T. Shen, L. Lipskaya, N. Miyamoto, Y. Suzuki, and N. Defer. Adenylyl cyclases structure, regulation and function in an enzyme superfamily. Mol. Cell. Endocrinol. 128 ... 

Sunahara, R.K., et al. Crystal structure of the adenylyl cyclase activator Gsa- Science 278 1943-1947, 1997. 

Zhang, G., Ruoho, A.E., Hurley, J.H. Structure of the adenylyl cyclase catalytic core. Nature 386 247-253, 1997. 

Table 4), but inhibit adenylyl cyclase by conforma-tionally distinct mechanisms (cf. Fig. 6) by binding within the catalytic cleft in unique structures (Fig. 7). 

Two metal sites were identified in the structure solved of the chimeiic AC5Ci AC2C2 adenylyl cyclase in complex with 3-L-2, 3 -dd-5 -ATP (cf. Figs. 5 and 7) One is... 

Soelaiman S, Wei BQ, Bergson P, Lee YS, Shen Y, Mrksich M, Shoichet BK, Tang WJ. Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough. J Biol Chem 2003 278 25990-7. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

G proteins regulate intracellular concentrations of second messengers. G proteins control intracellular cAMP concentrations by mediating the ability of neurotransmitters to activate or inhibit adenylyl cyclase. The mechanism by which neurotransmitters stimulate adenylyl cyclase is well known. Activation of those neurotransmitter receptors that couple to Gs results in the generation of free G(IS subunits, which bind to and thus directly activate adenylyl cyclase. In addition, free Py-subunit complexes activate certain subtypes of adenylyl cyclase (see Ch. 21). A similar mechanism appears to be the case for G(IO f, a type of G protein structurally related to G that is enriched in olfactory epithelium and striatum (Ch. 50). 

The 12-transmembrane-spanning domain topology of the adenylyl cyclase enzymes is similar to that found in the ABC family of transporters (see Ch. 5), which includes the cystic fibrosis transmembrane rectifier and the P-glyco-protein. However, there is currently no convincing evidence of a transporter or channel function for mammalian adenylyl cyclases. The structural similarity may indicate that these functionally divergent protein families are derived in an evolutionary sense from related proteins. 

Krupinski, J., Coussen, F. and Bakalyar, H. Adenylyl cyclase amino acid sequence possible channel- or transporter-like structure. Science 244 1558-1564,1989. 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

Fig. 5.19. GTP and GDP structures of transducin. The Ga,t subunit of transducin possesses—in contrast to Ras protein and to other small regulatory GTPases —an a-hehcal domain that hides and closes the G-nucleotide binding pocket. The conformational changes that accompany the transition from the inactive G t GDP form (a) into the active G t GTP form (b), are restricted to three structural sections that are known as switches I, II and III. Switch I includes the link of the a-helical domain with P2, switch II affects in particular hehx a2, and switch III, the pS—a3 loop. Switch III includes a sequence that is characteristic for the a-subunits of the heterotrimeric G-proteins. The conformational changes of switches II and III affect structural sections that are assumed to be binding sites for the effector molecule adenylyl cyclase (AC) and the y-subunit of cGMP-dependent phosphodiesterase (PDEy), based on mutation experiments and biochemical investigations. MOLSKRIPT representation according to Krauhs, (1991).

Despite the central importance of adenylyl cyclase for hormonal signal transduction, its structural and functional characterization is incomplete. In mammals, at least 9 dif-... 

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