Vanhooke Janeen L, Tadi Bulli Padmaja, Benning Matthew M, Plum Lori A, DeLuca Hector F
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. doi: 10.1016/j.abb.2006.11.029. Epub 2006 Dec 12.
We have successfully prepared E- and Z- isomers of 17-20 dehydro analogs of 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD). Both isomers bind to the recombinant rat vitamin D receptor (VDR) with high affinity. The Z-isomer (Vit-III 17-20Z) displays activity in vivo and in vitro that is similar to 2MD. The in vitro activity of the E-isomer (Vit-III 17-20E) is comparable to the natural hormone, though in vivo this analog is significantly less calcemic. Crystal structures of the rat VDR ligand binding domain complexed with the analogs demonstrate that the Vit-III 17-20Z analog is oriented almost identically to 2MD, with only minor differences induced by the planar configuration around the C17-C20 double bond. The Vit-III 17-20E analog is oriented in a conformation distinct from both 2MD and the natural hormone. The structural comparisons suggest that the position of C21 in the ligand binding site may be an important determinant of biological activity.
我们已成功制备出2-亚甲基-19-降-(20S)-1α,25-二羟基维生素D3（2MD）的17 - 20脱氢类似物的E型和Z型异构体。两种异构体均以高亲和力与重组大鼠维生素D受体（VDR）结合。Z型异构体（Vit-III 17 - 20Z）在体内和体外均表现出与2MD相似的活性。E型异构体（Vit-III 17 - 20E）的体外活性与天然激素相当，不过在体内该类似物的血钙升高作用明显较弱。与这些类似物复合的大鼠VDR配体结合结构域的晶体结构表明，Vit-III 17 - 20Z类似物的取向与2MD几乎完全相同，仅C17 - C20双键周围平面构型引起微小差异。Vit-III 17 - 20E类似物的取向构象与2MD和天然激素均不同。结构比较表明，配体结合位点中C21的位置可能是生物活性的重要决定因素。
