Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.
Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.
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DOI：
10.1021/bi981197z
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发表时间：
1998-11
期刊：
影响因子：
2.9
通讯作者：
C. Strickland;W. Windsor;R. Syto;Lynn Wang;R. Bond;Zhanghua Wu;J. Schwartz;H. Le;L. Beese;P. Weber
中科院分区：
文献类型：
--
作者：
C. Strickland;W. Windsor;R. Syto;Lynn Wang;R. Bond;Zhanghua Wu;J. Schwartz;H. Le;L. Beese;P. Weber
acetyl- cys - val - il - selenomet - cooh和α -羟基法尼基膦酸（alphaHFP）配合大鼠法尼基蛋白转移酶（FPT）的晶体结构（space group P61, a = b = 174）。13 A, c = 69.71 A, alpha = beta = 90度，gamma = 120度，Rfactor = 21.8%, Rfree = 29.2%， 2.5 A分辨率)。在三元配合物中，结合的底物彼此和FPT酶在范德华接触范围内。alphaHFP在活性位点空腔中以扩展构象结合，其中带正电的侧链和溶剂分子与磷酸盐部分相互作用，芳香侧链排列在类异戊二烯链附近。结合的CaaX肽的主链采用延伸构象，侧链与FPT和alphaHFP相互作用。结合肽的半胱氨酸硫与活性位点锌相协调。总的来说，肽的结合和识别似乎是由侧链相互作用主导的。对三联配合物和未配体FPT结构的比较[Park， H., Boduluri， S., Moomaw， J., Casey， P., and Beese， L. (1997) Science 275, 1800-1804]表明，几个活性位点侧链的主要重排发生在底物结合时。
The crystallographic structure of acetyl-Cys-Val-Ile-selenoMet-COOH and alpha-hydroxyfarnesylphosphonic acid (alphaHFP) complexed with rat farnesyl protein transferase (FPT) (space group P61, a = b = 174. 13 A, c = 69.71 A, alpha = beta = 90 degrees, gamma = 120 degrees, Rfactor = 21.8%, Rfree = 29.2%, 2.5 A resolution) is reported. In the ternary complex, the bound substrates are within van der Waals contact of each other and the FPT enzyme. alphaHFP binds in an extended conformation in the active-site cavity where positively charged side chains and solvent molecules interact with the phosphate moiety and aromatic side chains pack adjacent to the isoprenoid chain. The backbone of the bound CaaX peptide adopts an extended conformation, and the side chains interact with both FPT and alphaHFP. The cysteine sulfur of the bound peptide coordinates the active-site zinc. Overall, peptide binding and recognition appear to be dominated by side-chain interactions. Comparison of the structures of the ternary complex and unliganded FPT [Park, H., Boduluri, S., Moomaw, J., Casey, P., and Beese, L. (1997) Science 275, 1800-1804] shows that major rearrangements of several active site side chains occur upon substrate binding.