5LSO
Crystal structure of SPF45 UHM domain with cyclic peptide inhibitor
Summary for 5LSO
| Entry DOI | 10.2210/pdb5lso/pdb |
| Descriptor | Splicing factor 45, LYS-SER-ARG-TRP-ASP-GLU (3 entities in total) |
| Functional Keywords | uhm domain, splicing-inhibitor complex, splicing/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 24712.35 |
| Authors | Jagtap, P.K.A.,Garg, D.,Sattler, M. (deposition date: 2016-09-05, release date: 2016-10-26, Last modification date: 2024-01-17) |
| Primary citation | 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 Cited by 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: 27753493DOI: 10.1021/acs.jmedchem.6b01118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.22 Å) |
Structure validation
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