Crystal structure of phosphodiesterase 4D and inhibitor complex
Crystal structure of phosphodiesterase 4D and inhibitor complex
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DOI：
10.1016/s0014-5793(02)03396-3
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发表时间：
2002-10-23
期刊：
影响因子：
3.5
通讯作者：
Lee, H
中科院分区：
文献类型：
--
作者：
Lee, ME;Markowitz, J;Lee, H
环核苷酸磷酸二酯酶（PDEs）通过降解细胞内第二信使、腺苷-3 '，5'-环磷酸或鸟苷-3 '，5'-环磷酸来调节生理过程。测定了PDE 4D催化结构域和结合抑制剂扎达维林的第一晶体结构。扎达维林结合到一个高度保守的口袋，包括催化金属结合位点。扎达维林仅填充活性部位口袋的一部分。包括咯利普兰、西洛司特和罗氟司特在内的更具选择性的PDE 4抑制剂具有额外的官能团，这些官能团可以利用剩余的空位来增加结合能和选择性。在晶体结构中，PDE 4D的催化结构域具有广泛的二聚化界面，包含在PDE 1、3、4、8和9中高度保守的残基。这些界面残基中的R358 D或D322 R的突变阻止了溶液中PDE 4D催化结构域的二聚化。(C)2002年由Elsevier Science B. V.代表欧洲生物化学学会联合会出版。
Cyclic nucleotide phosphodiesterases (PDEs) regulate physiological processes by degrading intracellular second messengers, adenosine-3',5'-cyclic phosphate or guanosine-3',5'-cyclic phosphate. The first crystal structure of PDE4D catalytic domain and a bound inhibitor, zardaverine, was determined. Zardaverine binds to a highly conserved pocket that includes the catalytic metal binding site. Zardaverine fills only a portion of the active site pocket. More selective PDE4 inhibitors including rolipram, cilomilast and roflumilast have additional functional groups that can utilize the remaining empty space for increased binding energy and selectivity. In the crystal structure, the catalytic domain of PDE4D possesses an extensive dimerization interface containing residues that are highly conserved in PDE1, 3, 4, 8 and 9. Mutations of R358D or D322R among these interface residues prohibit dimerization of the PDE4D catalytic domain in solution. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.