5K28

Structure of the unbound SH3 domain of MLK3

5K28 の概要

• エントリーDOI: 10.2210/pdb5k28/pdb
• 関連するPDBエントリー: 5K26
• 分子名称: Mitogen-activated protein kinase kinase kinase 11 (2 entities in total)
• 機能のキーワード: mlk3, sh3, phage display, signalling protein, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 13799.09

構造登録者

Kall, S.K.,Lavie, A. (登録日: 2016-05-18, 公開日: 2017-12-13, 最終更新日: 2023-09-27)

主引用文献

Kokoszka, M.E.,Kall, S.L.,Khosla, S.,McGinnis, J.E.,Lavie, A.,Kay, B.K.
Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3.
J. Biol. Chem., 293:13553-13565, 2018

PubMed Abstract: Mixed-lineage kinase 3 (MLK3; also known as MAP3K11) is a Ser/Thr protein kinase widely expressed in normal and cancerous tissues, including brain, lung, liver, heart, and skeletal muscle tissues. Its Src homology 3 (SH3) domain has been implicated in MLK3 autoinhibition and interactions with other proteins, including those from viruses. The MLK3 SH3 domain contains a six-amino-acid insert corresponding to the n-Src insert, suggesting that MLK3 may bind additional peptides. Here, affinity selection of a phage-displayed combinatorial peptide library for MLK3's SH3 domain yielded a 13-mer peptide, designated "MLK3 SH3-interacting peptide" (MIP). Unlike most SH3 domain peptide ligands, MIP contained a single proline. The 1.2-Å crystal structure of the MIP-bound SH3 domain revealed that the peptide adopts a β-hairpin shape, and comparison with a 1.5-Å apo SH3 domain structure disclosed that the n-Src loop in SH3 undergoes an MIP-induced conformational change. A 1.5-Å structure of the MLK3 SH3 domain bound to a canonical proline-rich peptide from hepatitis C virus nonstructural 5A (NS5A) protein revealed that it and MIP bind the SH3 domain at two distinct sites, but biophysical analyses suggested that the two peptides compete with each other for SH3 binding. Moreover, SH3 domains of MLK1 and MLK4, but not MLK2, also bound MIP, suggesting that the MLK1-4 family may be differentially regulated through their SH3 domains. In summary, we have identified two distinct peptide-binding sites in the SH3 domain of MLK3, providing critical insights into mechanisms of ligand binding by the MLK family of kinases.

PubMed: 29980598
DOI: 10.1074/jbc.RA117.000262

実験手法

X-RAY DIFFRACTION (1.5 Å)