Shimohigashi Y, Nose T, Yamauchi Y, Maeda I
Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka, Japan.
Biopolymers. 1999;51(1):9-17. doi: 10.1002/(SICI)1097-0282(1999)51:1<9::AID-BIP3>3.0.CO;2-5.
A novel type of conformationally restricted peptides with the structure of H-D-Xaa-Phe-NH-CH2-C6H5 has been developed as inhibitors of serine proteinase chymotrypsin. The D-Xaa-alkyl and Phe-phenyl groups resulted in a formation of the hydrophobic core due to the side-chain-side-chain CH/pie interaction. Their spatial proximity was evidenced by 400 MHz 1H-nmr measurements, observing large upfield shifts of proton signals of D-Xaa-alkyl and nuclear Over-hauser effect (NOE) enhancements between the D-Xaa-alkyl and Phe-phenyl groups. This conformational restriction brought by CH/pie interaction produced an inhibitory structure, in which the C-terminal amide-benzyl group fits the chymotrypsin S1 site and the hydrophobic core binds to the S2 site. The inhibitory conformation was demonstrated crystallographically for the complex between the dipeptide H-D-Leu-Phe-NH-CH2-C6H4(p-F) and gamma-chymotrypsin. Detailed structure-activity studies have substantiated the structure of dipeptides in the active center of the enzyme.
一种具有H-D-Xaa-Phe-NH-CH2-C6H5结构的新型构象受限肽已被开发用作丝氨酸蛋白酶胰凝乳蛋白酶的抑制剂。由于侧链-侧链CH/π相互作用，D-Xaa-烷基和Phe-苯基形成了疏水核心。通过400 MHz 1H-nmr测量证明了它们的空间接近性，观察到D-Xaa-烷基质子信号的大幅高场位移以及D-Xaa-烷基和Phe-苯基之间的核Overhauser效应（NOE）增强。这种由CH/π相互作用带来的构象限制产生了一种抑制性结构，其中C端酰胺-苄基适合胰凝乳蛋白酶的S1位点，疏水核心与S2位点结合。通过二肽H-D-Leu-Phe-NH-CH2-C6H4(p-F)与γ-胰凝乳蛋白酶之间的复合物的晶体学研究证实了抑制性构象。详细的构效关系研究证实了酶活性中心中二肽的结构。
