Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.
Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.
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DOI：
10.1042/bj20070970
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发表时间：
2007-12
期刊：
影响因子：
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通讯作者：
Huanchen Wang;M. Peng;Yi Chen;J. Geng;H. Robinson;M. Houslay;J. Cai;H. Ke
中科院分区：
文献类型：
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作者：
Huanchen Wang;M. Peng;Yi Chen;J. Geng;H. Robinson;M. Houslay;J. Cai;H. Ke
PDE 4（磷酸二酯酶-4）-选择性抑制剂作为治疗抑郁症和主要炎性疾病的潜在治疗剂已经引起了很多关注，但是它们的实际应用受到副作用的影响。副作用的一个可能原因是目前的PDE 4选择性抑制剂类似地抑制来自所有四个PDE 4亚家族的亚型。由于缺乏结构信息，PDE 4亚家族选择性抑制剂的开发受到阻碍。在本研究中，我们通过提供与PDE 4抑制剂NVP {4-[8-（3-硝基苯基）-[1，7]萘啶-6-基]苯甲酸}复合的PDE 4A、PDE 4 B和PDE 4D的催化结构域的晶体结构以及未配体的PDE 4C结构来纠正这一点。NVP以相同的构象与深cAMP底物口袋结合，并在每种情况下与相同的残基相互作用。然而，详细的结构比较显示显着的构象差异。尽管PDE 4 B和PDE 4D的活性位点基本相当，但PDE 4A显示出对底物和抑制剂结合至关重要的恒定谷氨酰胺残基旁边的残基的显著置换。PDE 4C似乎与其他PDE 4亚家族更远，某些关键残基是无序的。我们的分析为开发PDE 4亚家族选择性抑制剂提供了第一个结构基础。
PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP {4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid} as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.