Hübner, Melanie and Dixit, A. and Mou, T.-C. and Lushington, Gerald H. and Pinto, Cibele S. and Gille, A. and Geduhn, Jens and König, Burkhard and Sprang, S. R. and Seifert, Roland (2011) Structural Basis for the High-Affinity Inhibition of Mammalian Membranous Adenylyl Cyclase by 2`,3`-O-(N-Methylanthraniloyl)-Inosine 5`-Triphosphate. Molecular Pharmacology 80 (1), pp. 87-96.
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2',3'-O-(N-Methylanthraniloyl)-inosine 5'-triphosphate (MANT-ITP) is the most potent inhibitor of mammalian membranous adenylyl cyclase (mAC) 5 (AC5, Ki, 1 nM) yet discovered and surpasses the potency of 2',3'-O-(N-methylanthraniloyl)-guanosine 5'-triphosphate (MANT-GTP) 55-fold (Göttle et al., J Pharmacol Exp Ther 329:1156-1165 (2009)). AC5 inhibitors may be valuable drugs for treatment of heart failure. The aim of this study was to elucidate the structural basis for the high-affinity inhibition of mAC by MANT-ITP. MANT-ITP was a considerably more potent inhibitor of the purified catalytic domains VC1 and IIC2 of mAC than MANT-GTP (Ki, 0.7 nM versus 18 nM). Moreover, there was considerably more efficient fluorescence resonance energy transfer between W1020 of IIC2 and the MANT-group of MANT-ITP compared to MANT-GTP, indicating optimal interaction of the MANT-group of MANT-ITP with the hydrophobic pocket. The crystal structure of MANT-ITP in complex with the Gsalpha- and forskolin-activated catalytic domains VC1:IIC2 in comparison to the existing MANT-GTP crystal structure revealed only subtle differences in binding mode. The higher affinity of MANT-ITP to mAC compared to MANT-GTP is probably due to fewer stereochemical constraints upon the nucleotide base in the purine binding pocket, allowing a stronger interaction with the hydrophobic regions of IIC2 domain, as assessed by fluorescence spectroscopy. Stronger interaction is also achieved in the phosphate-binding site. The triphosphate group of MANT-ITP exhibits better metal coordination than the triphosphate group of MANT-GTP, as confirmed by molecular dynamics simulations. Collectively, the subtle differences in ligand structure have profound effects on affinity for mAC.
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann formerly Prof. Seifert)|
Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||12 Aug 2011 09:56|
|Last Modified:||16 Aug 2011 10:23|
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