mRNA cap recognition: Dominant role of enhanced stacking interactions between methylated bases and protein aromatic side chains

被引:92
作者
Hu, GH
Gershon, PD
Hodel, AE
Quiocho, FA [1 ]
机构
[1] Baylor Coll Med, Grad Program Struct & Computat Biol & Mol Biophys, Houston, TX 77030 USA
[2] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA
[4] Texas A&M Univ, Inst Biosci & Technol, Houston, TX 77030 USA
关键词
D O I
10.1073/pnas.96.13.7149
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We have determined, by high resolution x-raj analysis, 10 structures comprising the mRNA cap-specific methyltransferase VP39 or specific mutants thereof in the presence of methylated nucleobase analogs (N1-methyladenine, N3-methyladenine, N1-methylcytosine, N3-methylcytosine) and their unmethylated counterparts, or nucleoside N7-methylguanosine. Together with solution affinity studies and previous crystallographic data for N7-methylguanosine and its phosphorylated derivatives, these data demonstrate that only methylated, positively charged bases are bound, indicating that their enhanced stacking with two aromatic side chains of VP39 (Tyr 22 and Phe 180) plays a dominant role in cap recognition. Four key features characterize this stacking interaction: (i) near perfect parallel alignment between the sandwiched methylated bases and aromatic side chains, (ii) substantial areas of overlap in the two-stacked rings, (iii) a 3.4-Angstrom interplanar spacing within the overlapping region, and (iv) positive charge in the heterocyclic nucleobase.
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页码:7149 / 7154
页数:6
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