Comparative electrostatic analysis of adenylyl cyclase for isoform dependent regulation properties.
The enzyme adenylyl cyclase (AC) plays a pivotal role in a variety of signal transduction pathways inside the cell, where it catalyzes the cyclization of adenosine triphosphate (ATP) into the second-messenger cyclic adenosine monophosphate (cAMP). Among other roles, AC regulates processes involved in neural plasticity, innervation of smooth muscles of the heart and the endocrine system of the pancreas. The functional diversity of AC is manifested in its different isoforms, each having a specific regulation pattern. There is an increasing amount of data available concerning the regulatory properties of AC isoforms, however little is known about the interactions on a structural level. Here, we conducted a comparative electrostatic analysis of the catalytic domains of all nine transmembrane AC isoforms with the aim of detecting, verifying and predicting the binding sites of molecular regulators on AC. The results provide support for the positioning of the binding site of the inhibitory protein Giα at a pseudo-symmetric position to the stimulatory Gsα binding site. They also provide a structural interpretation of the Gβγ interaction with ACs 2, 4, and 7 and suggest a new binding site for RGS2. Comparison of the small molecule binding sites on AC shows that overall they have high electrostatic similarity, but regions of electrostatic differences are identified. These could provide a basis for the development of novel compounds with isoform-specific modulatory effects on AC. Proteins 2016; 84:1844-1858. © 2016 Wiley Periodicals, Inc.
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.|Institute of Pharmacy and Molecular Biotechnology (IPMB) Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
Rudi
R
Tong
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.|Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany.|Interdisciplinary Center for Scientific Computing (IWR) Heidelberg University, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany.
Rebecca C
RC
Wade
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.
Neil J
NJ
Bruce
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000067956:Adenylyl Cyclase Inhibitors / Q000737:chemistry*; D000262:Adenylyl Cyclases / Q000737:chemistry*; D020816:Amino Acid Motifs; D001665:Binding Sites; D020134:Catalytic Domain; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry*; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry*; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D020710:RGS Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000067956:Adenylyl Cyclase Inhibitors; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007527:Isoenzymes; D008024:Ligands; D020710:RGS Proteins; C087182:RGS2 protein, human; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases
G protein; adenylyl cyclase; bioinformatics; electrostatics; homology; macromolecular association; modeling; molecular recognition; protein-protein interactions; signaling