Huebner, Melanie and Dixit, Anshuman and Mou, Tung-Chung and Lushington, Gerald H. and Pinto, Cibele and Gille, Andreas and Geduhn, Jens and Koenig, Burkhard and Sprang, Stephen 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. ISSN 0026-895X,
Full text not available from this repository. (Request a copy)Abstract
2',3'-O-(N-Methylanthraniloyl)-ITP (MANT-ITP) is the most potent inhibitor of mammalian membranous adenylyl cyclase (mAC) 5 (AC5, K-i, 1 nM) yet discovered and surpasses the potency of MANT-GTP by 55-fold (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 (K-i, 0.7 versus 18 nM). Moreover, there was considerably more efficient fluorescence resonance energy transfer between Trp1020 of IIC2 and the MANT group of MANT-ITP compared with 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 G(s)alpha- and forskolin-activated catalytic domains VC1:IIC2 compared with the existing MANT-GTP crystal structure revealed only subtle differences in binding mode. The higher affinity of MANT-ITP to mAC compared with 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PHOSPHORUS-CONTAINING INHIBITORS; SOLUBLE GUANYLYL CYCLASE; NUCLEOSIDE 5'-TRIPHOSPHATES; NUCLEOTIDE INHIBITORS; DIFFERENTIAL INHIBITION; PYRIMIDINE NUCLEOTIDES; MOLECULAR-DYNAMICS; CATALYTIC SITE; X-RAY; BINDING; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | 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 |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Jun 2020 11:30 |
| Last Modified: | 08 Jun 2020 11:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20604 |
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