Ivancic Monika, Daly Roger J, Lyons Barbara A
Department of Biochemistry, University of Vermont College of Medicine Burlington, VT 05405, U.S.A.
J Biomol NMR. 2003 Nov;27(3):205-19. doi: 10.1023/a:1025498409113.
The solution structure of the hGrb7-SH2 domain in complex with a ten amino acid phosphorylated peptide ligand representative of the erbB2 receptor tyrosine kinase (pY1139) is presented as determined by nuclear magnetic resonance methods. The hGrb7-SH2 domain structure reveals the Src homology 2 domain topology consisting of a central beta-sheet capped at each end by an alpha-helix. The presence of a four residue insertion in the region between beta-strand E and the EF loop and resulting influences on the SH2 domain/peptide complex structure are discussed. The binding conformation of the erbB2 peptide is in a beta-turn similar to that found in phosphorylated tyrosine peptides bound to the Grb2-SH2 domain. To our knowledge this is only the second example of an SH2 domain binding its naturally occurring ligands in a turn, instead of extended, conformation. Close contacts between residues responsible for binding specificity in hGrb7-SH2 and the erbB2 peptide are characterized and the potential effect of mutation of these residues on the hGrb7-SH2 domain structure is discussed.
通过核磁共振方法确定了人源生长因子受体结合蛋白7（hGrb7）的SH2结构域与代表erbB2受体酪氨酸激酶（pY1139）的十氨基酸磷酸化肽配体形成的复合物的溶液结构。hGrb7-SH2结构域结构揭示了Src同源2结构域拓扑结构，其由中央β-折叠组成，两端各由一个α-螺旋封闭。讨论了在β-链E和EF环之间区域存在四个残基插入及其对SH2结构域/肽复合物结构的影响。erbB2肽的结合构象呈β-转角，类似于与Grb2-SH2结构域结合的磷酸化酪氨酸肽中的构象。据我们所知，这是SH2结构域以转角而非伸展构象结合其天然配体的第二个例子。对hGrb7-SH2中负责结合特异性的残基与erbB2肽之间的紧密接触进行了表征，并讨论了这些残基突变对hGrb7-SH2结构域结构的潜在影响。
