Binding affinity difference induced by the stereochemistry of the sulfoxide bridge of the cyclic peptide inhibitors of Grb2-SH2 domain: NMR studies for the structural origin | |
Shi, YH![]() | |
刊名 | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2005-05-20 | |
卷号 | 330期号:4页码:1254-1261 |
关键词 | solution structure NMR dynamics Grb2-SH2 domain inhibitors cyclic peptide signal transduction chiral sulfoxide configuration |
ISSN号 | 0006-291X |
DOI | 10.1016/j.bbrc.2005.03.110 |
文献子类 | Article |
英文摘要 | The SAR study on a phage library-derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain indicates that the configuration of the cyclization linkage is crucial for assuming the active binding conformation. When the thioether linkage was oxidized to the two chiral sulfoxides, the R-configured sulfoxide-cyclized peptide displayed 10-30 times more potency than the corresponding S-configured one in binding affinity to the Grb2-SH2 domain. In this paper, the solution structures of such a pair of sulfoxide-bridged cyclic peptide diastereoisomers, i.e., cyclo[CH2CO-Gla(1)-L-Y-E-N-V-G-NPG-Y-(R/S)C(O)(10)]-amide, were determined by NMR and molecular dynamics simulation. Results indicate that the consensus sequence of Y-3-E-4-N-5-V-6 in both diastereoisomers adopt a U-turn conformation; however, the R-configured peptide forms an extended structure with a circular backbone conformation, while the S-configured isomer forms a compact structure with key residues buried inside the molecule. The average root-mean-square deviations were found to be 0.756 and 0.804 angstrom, respectively. It is apparent that the chiral S -> O group played a key role in the solution structures of the sulfoxide-bridged cyclic peptides. The R-sulfoxide group forms an intramolecular hydrogen bond with the C-terminal amide, conferring a more rigid conformation with all residues protruding outside except for Leu2, in which the Gla1 and Tyr3 share an overlapping function as previous SAR studies proposed. Additionally, the extended structure endows a more hydrophilic binding surface of the R-configured peptide to facilitate its capture by its targeted protein. In comparison, the S-configured sulfoxide was embedded inside the ligand peptide leading to a compact structure, in which the essential residues of Gla1, Tyr3, and Asn5 form multiple intramolecular hydrogen bonds resulting in an unfavorable conformational change and a substantial loss of the interaction with the protein. The solution structures disclosed by our NMR and molecular dynamics simulation studies provide a molecular basis for understanding how the chirality of the cyclization linkage remarkably discriminates in terms of the binding affinity, thus advancing the rational design of potent non-phosphorylated inhibitors of Grb2-SH2 domain as antitumor agents. Published by Elsevier Inc. |
WOS关键词 | SH2 DOMAIN ; NONPHOSPHORYLATED INHIBITOR ; CHEMICAL-SHIFTS ; ANTAGONISTS ; PROTEINS ; REQUIREMENTS ; DYNAMICS ; ENERGY ; CELLS |
WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
语种 | 英语 |
出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
WOS记录号 | WOS:000228566300035 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/273871] ![]() |
专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
通讯作者 | Long, YQ |
作者单位 | 1.CAS, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, State Key Lab Drug Res,Dept Synth Chem, Shanghai 201203, Peoples R China 2.CAS, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Dept Analyt Sci, Shanghai 201203, Peoples R China 3.CAS, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 4.NCI, Med Chem Lab, FCRDC, NIH, Frederick, MD 21702 USA |
推荐引用方式 GB/T 7714 | Shi, YH,Song, YL,Lin, DH,et al. Binding affinity difference induced by the stereochemistry of the sulfoxide bridge of the cyclic peptide inhibitors of Grb2-SH2 domain: NMR studies for the structural origin[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2005,330(4):1254-1261. |
APA | Shi, YH.,Song, YL.,Lin, DH.,Tan, JZ.,Roller, PP.,...&Song, GQ.(2005).Binding affinity difference induced by the stereochemistry of the sulfoxide bridge of the cyclic peptide inhibitors of Grb2-SH2 domain: NMR studies for the structural origin.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,330(4),1254-1261. |
MLA | Shi, YH,et al."Binding affinity difference induced by the stereochemistry of the sulfoxide bridge of the cyclic peptide inhibitors of Grb2-SH2 domain: NMR studies for the structural origin".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 330.4(2005):1254-1261. |
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