Narayana N, Diller T C, Koide K, Bunnage M E, Nicolaou K C, Brunton L L, Xuong N H, Ten Eyck L F, Taylor S S
The Howard Hughes Medical Institute, Department of Biology, University of California, San Diego, La Jolla, USA.
Biochemistry. 1999 Feb 23;38(8):2367-76. doi: 10.1021/bi9820659.
Endogenous protein kinase inhibitors are essential for a wide range of physiological functions. These endogenous inhibitors may mimic peptide substrates as in the case of the heat-stable protein kinase inhibitor (PKI), or they may mimic nucleotide triphosphates. Natural product inhibitors, endogenous to the unique organisms producing them, can be potent exogenous inhibitors against foreign protein kinases. Balanol is a natural product inhibitor exhibiting low nanomolar Ki values against serine and threonine specific kinases, while being ineffective against protein tyrosine kinases. To elucidate balanol's specific inhibitory effects and provide a basis for understanding inhibition-regulated biological processes, a 2.1 A resolution crystal structure of balanol in complex with cAMP-dependent protein kinase (cAPK) was determined. The structure reveals conserved binding regions and displays extensive complementary interactions between balanol and conserved cAPK residues. This report describes the structure of a protein kinase crystallized with a natural ATP mimetic in the absence of metal ions and peptide inhibitor.
内源性蛋白激酶抑制剂对于广泛的生理功能至关重要。这些内源性抑制剂可能会模拟肽底物，如热稳定蛋白激酶抑制剂（PKI）的情况，或者它们可能会模拟三磷酸核苷酸。对于产生它们的独特生物体而言是内源性的天然产物抑制剂，可以成为针对外源蛋白激酶的有效抑制剂。巴拉诺醇是一种天然产物抑制剂，对丝氨酸和苏氨酸特异性激酶表现出低纳摩尔的Ki值，而对蛋白酪氨酸激酶无效。为了阐明巴拉诺醇的特异性抑制作用，并为理解抑制调节的生物过程提供基础，测定了巴拉诺醇与环磷酸腺苷依赖性蛋白激酶（cAPK）复合物的2.1埃分辨率晶体结构。该结构揭示了保守的结合区域，并展示了巴拉诺醇与保守的cAPK残基之间广泛的互补相互作用。本报告描述了在没有金属离子和肽抑制剂的情况下，与天然ATP模拟物一起结晶的蛋白激酶的结构。
