3KZ0

MCL-1 complex with MCL-1-specific selected peptide

3KZ0 の概要

• エントリーDOI: 10.2210/pdb3kz0/pdb
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, Mcl-1 specific peptide MB7, ZINC ION, ... (5 entities in total)
• 機能のキーワード: bcl-2, bh3, mitochondrion, apoptosis, anti-apoptotic
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane ; Single-pass membrane protein : Q07820
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42020.77

構造登録者

Dutta, S.,Fire, E.,Grant, R.A.,Sauer, R.T.,Keating, A.E. (登録日: 2009-12-07, 公開日: 2010-05-05, 最終更新日: 2024-11-06)

主引用文献

Dutta, S.,Gulla, S.,Chen, T.S.,Fire, E.,Grant, R.A.,Keating, A.E.
Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL.
J.Mol.Biol., 398:747-762, 2010

PubMed Abstract: Interactions among Bcl-2 family proteins are important for regulating apoptosis. Prosurvival members of the family interact with proapoptotic BH3 (Bcl-2-homology-3)-only members, inhibiting execution of cell death through the mitochondrial pathway. Structurally, this interaction is mediated by binding of the alpha-helical BH3 region of the proapoptotic proteins to a conserved hydrophobic groove on the prosurvival proteins. Native BH3-only proteins exhibit selectivity in binding prosurvival members, as do small molecules that block these interactions. Understanding the sequence and structural basis of interaction specificity in this family is important, as it may allow the prediction of new Bcl-2 family associations and/or the design of new classes of selective inhibitors to serve as reagents or therapeutics. In this work, we used two complementary techniques--yeast surface display screening from combinatorial peptide libraries and SPOT peptide array analysis--to elucidate specificity determinants for binding to Bcl-x(L)versus Mcl-1, two prominent prosurvival proteins. We screened a randomized library and identified BH3 peptides that bound to either Mcl-1 or Bcl-x(L) selectively or to both with high affinity. The peptides competed with native ligands for binding into the conserved hydrophobic groove, as illustrated in detail by a crystal structure of a specific peptide bound to Mcl-1. Mcl-1-selective peptides from the screen were highly specific for binding Mcl-1 in preference to Bcl-x(L), Bcl-2, Bcl-w, and Bfl-1, whereas Bcl-x(L)-selective peptides showed some cross-interaction with related proteins Bcl-2 and Bcl-w. Mutational analyses using SPOT arrays revealed the effects of 170 point mutations made in the background of a peptide derived from the BH3 region of Bim, and a simple predictive model constructed using these data explained much of the specificity observed in our Mcl-1 versus Bcl-x(L) binders.

PubMed: 20363230
DOI: 10.1016/j.jmb.2010.03.058

実験手法

X-RAY DIFFRACTION (2.349 Å)