5LSO

Crystal structure of SPF45 UHM domain with cyclic peptide inhibitor

5LSO の概要

• エントリーDOI: 10.2210/pdb5lso/pdb
• 分子名称: Splicing factor 45, LYS-SER-ARG-TRP-ASP-GLU (3 entities in total)
• 機能のキーワード: uhm domain, splicing-inhibitor complex, splicing/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 24712.35

構造登録者

Jagtap, P.K.A.,Garg, D.,Sattler, M. (登録日: 2016-09-05, 公開日: 2016-10-26, 最終更新日: 2024-01-17)

主引用文献

Jagtap, P.K.,Garg, D.,Kapp, T.G.,Will, C.L.,Demmer, O.,Luhrmann, R.,Kessler, H.,Sattler, M.
Rational Design of Cyclic Peptide Inhibitors of U2AF Homology Motif (UHM) Domains To Modulate Pre-mRNA Splicing.
J. Med. Chem., 59:10190-10197, 2016

PubMed Abstract: U2AF homology motifs (UHMs) are atypical RNA recognition motif domains that mediate critical protein-protein interactions during the regulation of alternative pre-mRNA splicing and other processes. The recognition of UHM domains by UHM ligand motif (ULM) peptide sequences plays important roles during early steps of spliceosome assembly. Splicing factor 45 kDa (SPF45) is an alternative splicing factor implicated in breast and lung cancers, and splicing regulation of apoptosis-linked pre-mRNAs by SPF45 was shown to depend on interactions between its UHM domain and ULM motifs in constitutive splicing factors. We have developed cyclic peptide inhibitors that target UHM domains. By screening a focused library of linear and cyclic peptides and performing structure-activity relationship analysis, we designed cyclic peptides with 4-fold improved binding affinity for the SPF45 UHM domain compared to native ULM ligands and 270-fold selectivity to discriminate UHM domains from alternative and constitutive splicing factors. These inhibitors are useful tools to modulate and dissect mechanisms of alternative splicing regulation.

PubMed: 27753493
DOI: 10.1021/acs.jmedchem.6b01118

実験手法

X-RAY DIFFRACTION (2.22 Å)