1CS4

COMPLEX OF GS-ALPHA WITH THE CATALYTIC DOMAINS OF MAMMALIAN ADENYLYL CYCLASE: COMPLEX WITH 2'-DEOXY-ADENOSINE 3'-MONOPHOSPHATE, PYROPHOSPHATE AND MG

1CS4 の概要

• エントリーDOI: 10.2210/pdb1cs4/pdb
• 関連するPDBエントリー: 1cul
• 分子名称: TYPE V ADENYLATE CYCLASE, 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE, TYPE II ADENYLATE CYCLASE, ... (11 entities in total)
• 機能のキーワード: complex (lyase-hydrolase), hydrolase, signal transducing protein, cyclase, effector enzyme, lyase-hydrolase complex, lyase-lyase-signaling protein complex, lyase/lyase/signaling protein
• 由来する生物種: Canis lupus familiaris (dog); 詳細
• 細胞内の位置: Membrane; Multi-pass membrane protein: P30803 P26769; Cell membrane; Lipid-anchor (By similarity): P04896
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 96944.54

構造登録者

Tesmer, J.J.G.,Dessauer, C.A.,Sunahara, R.K.,Johnson, R.A.,Gilman, A.G.,Sprang, S.R. (登録日: 1999-08-16, 公開日: 2001-01-10, 最終更新日: 2024-02-07)

主引用文献

Tesmer, J.J.,Dessauer, C.W.,Sunahara, R.K.,Murray, L.D.,Johnson, R.A.,Gilman, A.G.,Sprang, S.R.
Molecular basis for P-site inhibition of adenylyl cyclase.
Biochemistry, 39:14464-14471, 2000

PubMed Abstract: 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.

PubMed: 11087399
DOI: 10.1021/bi0015562

実験手法

X-RAY DIFFRACTION (2.5 Å)