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spinqualitylabelsall models 1cul, resolution 2.4Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH 2',5'-DIDEOXY-ADENOSINE 3'-TRIPHOSPHATE AND MG

Overview

P-site inhibitors are adenosine and adenine nucleotide analogues that, inhibit adenylyl cyclase, the effector enzyme that catalyzes the synthesis, of cyclic AMP from ATP. Some of these inhibitors may represent, physiological regulators of adenylyl cyclase, and the most potent may, ultimately serve as useful therapeutic agents. Described here are crystal, structures of the catalytic core of adenylyl cyclase complexed with two, such P-site inhibitors, 2'-deoxyadenosine 3'-monophosphate (2'-d-3'-AMP), and 2',5'-dideoxyadenosine 3'-triphosphate (2',5'-dd-3'-ATP). Both, inhibitors bind in the active site yet exhibit non- or uncompetitive, patterns of inhibition. While most P-site inhibitors require pyrophosphate, (PP(i)) as a coinhibitor, 2',5'-dd-3'-ATP is a potent inhibitor by itself., The crystal structure reveals that this inhibitor exhibits two binding, modes: one with the nucleoside moiety bound to the nucleoside binding, pocket of the enzyme and the other with the beta and gamma phosphates, bound to the pyrophosphate site of the 2'-d-3'-AMP.PP(i) complex. A single, metal binding site is observed in the complex with 2'-d-3'-AMP, whereas, two are observed in the complex with 2', 5'-dd-3'-ATP. Even though P-site, inhibitors are typically 10 times more potent in the presence of Mn(2+), the electron density maps reveal no inherent preference of either metal, site for Mn(2+) over Mg(2+). 2',5'-dd-3'-ATP binds to the catalytic core, of adenylyl cyclase with a K(d) of 2.4 microM in the presence of Mg(2+), and 0.2 microM in the presence of Mn(2+). Pyrophosphate does not compete, with 2',5'-dd-3'-ATP and enhances inhibition.

About this Structure

1CUL is a Protein complex structure of sequences from Bos taurus, Canis lupus familiaris and Rattus norvegicus with MG, CL, GSP, FOK, 103, 3PO and MES as ligands. Active as Adenylate cyclase, with EC number 4.6.1.1 Full crystallographic information is available from OCA.

Reference

Molecular basis for P-site inhibition of adenylyl cyclase., Tesmer JJ, Dessauer CW, Sunahara RK, Murray LD, Johnson RA, Gilman AG, Sprang SR, Biochemistry. 2000 Nov 28;39(47):14464-71. PMID:11087399

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