8TLW
Crystal structure of MBP and AF9 AHD fusion protein 3AQA in complex with peptidomimetic inhibitor 28
Summary for 8TLW
| Entry DOI | 10.2210/pdb8tlw/pdb |
| Related PRD ID | PRD_900001 |
| Descriptor | MBP and AF9 AHD fusion protein 3AQA, peptidomimetic inhibitor 28, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (4 entities in total) |
| Functional Keywords | mll fusion super elongation complex (sec) acute lymphoblastic leukemia acute myeloid leukemia, translation |
| Biological source | Escherichia coli K-12 More |
| Total number of polymer chains | 2 |
| Total formula weight | 50051.63 |
| Authors | Yang, Y.,Nikolovska-Coleska, Z. (deposition date: 2023-07-27, release date: 2024-05-29, Last modification date: 2024-09-11) |
| Primary citation | Yang, Y.,Ahmad, E.,Premkumar, V.,Liu, A.,Ashikur Rahman, S.M.,Nikolovska-Coleska, Z. Structural studies of intrinsically disordered MLL-fusion protein AF9 in complex with peptidomimetic inhibitors. Protein Sci., 33:e5019-e5019, 2024 Cited by PubMed Abstract: AF9 (MLLT3) and its paralog ENL(MLLT1) are members of the YEATS family of proteins with important role in transcriptional and epigenetic regulatory complexes. These proteins are two common MLL fusion partners in MLL-rearranged leukemias. The oncofusion proteins MLL-AF9/ENL recruit multiple binding partners, including the histone methyltransferase DOT1L, leading to aberrant transcriptional activation and enhancing the expression of a characteristic set of genes that drive leukemogenesis. The interaction between AF9 and DOT1L is mediated by an intrinsically disordered C-terminal ANC1 homology domain (AHD) in AF9, which undergoes folding upon binding of DOT1L and other partner proteins. We have recently reported peptidomimetics that disrupt the recruitment of DOT1L by AF9 and ENL, providing a proof-of-concept for targeting AHD and assessing its druggability. Intrinsically disordered proteins, such as AF9 AHD, are difficult to study and characterize experimentally on a structural level. In this study, we present a successful protein engineering strategy to facilitate structural investigation of the intrinsically disordered AF9 AHD domain in complex with peptidomimetic inhibitors by using maltose binding protein (MBP) as a crystallization chaperone connected with linkers of varying flexibility and length. The strategic incorporation of disulfide bonds provided diffraction-quality crystals of the two disulfide-bridged MBP-AF9 AHD fusion proteins in complex with the peptidomimetics. These successfully determined first series of 2.1-2.6 Å crystal complex structures provide high-resolution insights into the interactions between AHD and its inhibitors, shedding light on the role of AHD in recruiting various binding partner proteins. We show that the overall complex structures closely resemble the reported NMR structure of AF9 AHD/DOT1L with notable difference in the conformation of the β-hairpin region, stabilized through conserved hydrogen bonds network. These first series of AF9 AHD/peptidomimetics complex structures are providing insights of the protein-inhibitor interactions and will facilitate further development of novel inhibitors targeting the AF9/ENL AHD domain. PubMed: 38747396DOI: 10.1002/pro.5019 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.106 Å) |
Structure validation
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