Gille, Andreas and Guo, Jian-Xin and Mou, Tung-Chung and Doughty, Michael B. and Lushington, Gerald H. and Seifert, Roland (2005) Differential interactions of G-proteins and adenylyl cyclase with nucleoside 5 '-triphosphates, nucleoside 5 '-[gamma-thio]triphosphates and nucleoside 5 '-[beta,gamma-imido]triphosphates. BIOCHEMICAL PHARMACOLOGY, 71 (1-2). pp. 89-97. ISSN 0006-2952, 1873-2968
Full text not available from this repository. (Request a copy)Abstract
The regulatory G-proteins of adenylyl cyclase (AC), G(1) and G(s), are not only activated by GTP and the stable GTP analogs, guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) and guanosine 5'-[beta,gamma-imido]triphosphate (GppNHp), but also by hypoxanthine, xanthine, uracil and cytidine nucleotides. The latter nucleotides were previously used to analyze distinct active G-protein states. Surprisingly, recent studies have shown that inosine 5'-[gamma-thio]triphosphate and uridine 5'-[gamma-thio]triphosphate can also inhibit AC directly. Therefore, we systematically compared the interactions of nucleoside 5'-triphosphates (NTPs), nucleoside 5'-[gamma-thio]triphosphates (NTP gamma Ss) and nucleoside 5'-(beta,gamma-imido]triphosphates (NppNHps) with G1, G, and AC. NTP gamma Ss exhibited up to 26,000-fold higher affinity for G-proteins than NTPs and NppNHps. NTP gamma Ss were up to 150-fold more potent direct AC inhibitors than NTPs and NppNHps. G-proteins exhibited striking preference for guanine nucleotides compared to other purine and pyrimidine nucleotides, whereas base-selectivity of various ACs, particularly the purified catalytic subunits C1.C2, was rather poor. GTP, GTP-YS and GppNHp exhibited much higher selectivity for G-proteins relative to AC than all other purine and pyrimidine nucleotides. We have energetically characterized the interactions of purine and pyrimidine nucleotides with AC in silico, constructing pharmacophore models that correlate well with experimental affinities and have elucidated specific amino acid residues with greatest influence on nucleotide binding. Collectively, both G-proteins and ACs bind purine and pyrimidine nucleotides, with G-proteins showing much higher base-selectivity than AC. Thus, direct inhibitory effects of nucleotides on AC should be understood and considered when probing distinct active G-protein states with non-guanine nucleotides. (c) 2005 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RETINAL G-PROTEIN; DISTINCT INTERACTIONS; CYTOSOLIC DOMAINS; LYMPHOMA-CELLS; GDP-AFFINITY; NUCLEOTIDES; RECEPTOR; INHIBITION; MEMBRANES; GTP; G-protein; adenylyl cyclase; nucleoside 5 '-triphosphate; nucleoside 5 '-[gamma-thio]triphosphate; nucleoside 5 '-[beta-gamma-imido]triphosphate; molecular docking; pharmacophore model |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Apr 2021 08:26 |
| Last Modified: | 14 Apr 2021 08:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/35312 |
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