Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90
Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90
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DOI：
10.1016/s1074-5521(03)00075-9
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发表时间：
2003-04-01
影响因子：
--
通讯作者：
Santi, DV
中科院分区：
文献类型：
--
作者：
Jez, JM;Chen, JCH;Santi, DV
Hsp90是一个有吸引力的化疗靶点，因为它伴随着多种信号转导途径中发现的蛋白质折叠。我们描述了人Hsp90alpha（残基9-236）与17-去甲氧基-17- n， n -二甲氨基乙基氨基格尔达霉素（17-DMAG）配合的1.75 A分辨率晶体结构。与格尔达霉素和17-二甲氨基乙基指向溶剂相比，该结构揭示了17-取代基与蛋白质之间的一系列相互作用的改变，但在其他方面与报道的与格尔达霉素配合物相似。靶向分子动力学模拟和能量分析表明，格尔达霉素与Hsp90结合时发生了两大构象变化，其中转化的关键步骤是大环酰胺键的反式到顺式构象变化。我们推测，限制在基态的顺式酰胺的17-DMAG类似物可以显著增加对Hsp90的亲和力。
Hsp90 is an attractive chemotherapeutic target because it chaperones the folding of proteins found in multiple signal transduction pathways. We describe the 1.75 A resolution crystal structure of human Hsp90alpha (residues 9-236) complexed with 17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG). The structure revealed an altered set of interactions between the 17-substituent and the protein compared to geldanamycin and the 17-dimethylaminoethyl moiety pointing into solvent, but otherwise was similar to that reported for the complex with geldanamycin. Targeted molecular dynamics simulations and energetic analysis indicate that geldanamycin undergoes two major conformational changes when it binds Hsp90, with the key step of the conversion being the trans to cis conformational change of the macrocycle amide bond. We speculate that 17-DMAG analogs constrained to a cis-amide in the ground state could provide a significant increase in affinity for Hsp90.