8BEA

Crystal structure of SOS1-HRas-peptidomimetic10

8BEA の概要

• エントリーDOI: 10.2210/pdb8bea/pdb
• 分子名称: GTPase HRas, Son of sevenless homolog 1, SOS1-HRas-peptidomimetic10, ... (4 entities in total)
• 機能のキーワード: complex, stabilizer, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 81491.60

構造登録者

Fischer, B.,Wohlkonig, A.,Steyaert, J. (登録日: 2022-10-21, 公開日: 2023-04-26, 最終更新日: 2023-11-15)

主引用文献

Van Holsbeeck, K.,Fischer, B.,Gonzalez, S.,Gadais, C.,Versees, W.,Martins, J.C.,Martin, C.,Wohlkonig, A.,Steyaert, J.,Ballet, S.
Nanobody Loop Mimetics Enhance Son of Sevenless 1-Catalyzed Nucleotide Exchange on RAS.
Angew.Chem.Int.Ed.Engl., 62:e202219095-e202219095, 2023

PubMed Abstract: RAS proteins control various intracellular signaling networks. Mutations at specific locations were shown to stabilize their active guanosine triphosphate (GTP)-bound state, which is associated with the development of multiple cancers. An attractive approach to modulate RAS signaling is through its regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). With the recent discovery of Nanobody14 (Nb14), which potently enhances SOS1-catalyzed nucleotide exchange on RAS, we explored the feasibility of developing peptide mimetics by structurally mimicking the complementarity-determining region 3 (CDR3). Guided by a biochemical GEF assay and X-ray co-crystal structures, successive rounds of optimization and gradual conformational rigidification led to CDR3 mimetics showing half of the maximal activation potential of Nb14 with an EC value of 29 μM. Altogether, this study demonstrated that peptides able to modulate a protein-protein interaction can be obtained by structural mimicry of a Nb paratope.

PubMed: 37067463
DOI: 10.1002/anie.202219095

実験手法

X-RAY DIFFRACTION (2.47 Å)