2gvd
From Proteopedia
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'''Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn''' | '''Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn''' | ||
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[[Category: Mou, T C.]] | [[Category: Mou, T C.]] | ||
[[Category: Sprang, S R.]] | [[Category: Sprang, S R.]] | ||
| - | [[Category: | + | [[Category: Adenylyl cyclase]] |
| - | [[Category: | + | [[Category: Gsa]] |
| - | [[Category: | + | [[Category: Tnp-atp]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:35:04 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 02:35, 4 May 2008
Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn
Overview
Membrane adenylyl cyclases (mACs) play an important role in signal transduction and are therefore potential drug targets. Earlier, we identified 2',3'-O-(N-methylanthraniloyl) (MANT)-substituted purine nucleotides as a novel class of highly potent competitive mAC inhibitors (Ki values in the 10 nM range). MANT nucleotides discriminate among various mAC isoforms through differential interactions with a binding pocket localized at the interface between the C1 and C2 domains of mAC. In this study, we examine the structure/activity relationships for 2',3'-substituted nucleotides and compare the crystal structures of mAC catalytic domains (VC1:IIC2) bound to MANT-GTP, MANT-ATP, and 2',3'-(2,4,6-trinitrophenyl) (TNP)-ATP. TNP-substituted purine and pyrimidine nucleotides inhibited VC1:IIC2 with moderately high potency (Ki values in the 100 nM range). Elongation of the linker between the ribosyl group and the MANT group and substitution of N-adenine atoms with MANT reduces inhibitory potency. Crystal structures show that MANT-GTP, MANT-ATP, and TNP-ATP reside in the same binding pocket in the VC1:IIC2 protein complex, but there are substantial differences in interactions of base, fluorophore, and polyphosphate chain of the inhibitors with mAC. Fluorescence emission and resonance transfer spectra also reflect differences in the interaction between MANT-ATP and VC1:IIC2 relative to MANT-GTP. Our data are indicative of a three-site mAC pharmacophore; the 2',3'-O-ribosyl substituent and the polyphosphate chain have the largest impact on inhibitor affinity and the nucleotide base has the least. The mAC binding site exhibits broad specificity, accommodating various bases and fluorescent groups at the 2',3'-O-ribosyl position. These data should greatly facilitate the rational design of potent, isoform-selective mAC inhibitors.
About this Structure
2GVD is a Protein complex structure of sequences from Bos taurus, Canis lupus familiaris and Rattus norvegicus. Full crystallographic information is available from OCA.
Reference
Broad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors., Mou TC, Gille A, Suryanarayana S, Richter M, Seifert R, Sprang SR, Mol Pharmacol. 2006 Sep;70(3):878-86. Epub 2006 Jun 9. PMID:16766715 Page seeded by OCA on Sun May 4 05:35:04 2008
