8I8Y
A mutant of the C-terminal complex of proteins 4.1G and NuMA
Summary for 8I8Y
| Entry DOI | 10.2210/pdb8i8y/pdb |
| Descriptor | Engineered protein (2 entities in total) |
| Functional Keywords | a computational design mutant of a fusion protein from the c terminal of 4.1g and numa, de novo protein |
| Biological source | synthetic construct More |
| Total number of polymer chains | 2 |
| Total formula weight | 16392.75 |
| Authors | |
| Primary citation | Hu, X.,Xu, Y.,Wang, C.,Liu, Y.,Zhang, L.,Zhang, J.,Wang, W.,Chen, Q.,Liu, H. Combined prediction and design reveals the target recognition mechanism of an intrinsically disordered protein interaction domain. Proc.Natl.Acad.Sci.USA, 120:e2305603120-e2305603120, 2023 Cited by PubMed Abstract: An increasing number of protein interaction domains and their targets are being found to be intrinsically disordered proteins (IDPs). The corresponding target recognition mechanisms are mostly elusive because of challenges in performing detailed structural analysis of highly dynamic IDP-IDP complexes. Here, we show that by combining recently developed computational approaches with experiments, the structure of the complex between the intrinsically disordered C-terminal domain (CTD) of protein 4.1G and its target IDP region in NuMA can be dissected at high resolution. First, we carry out systematic mutational scanning using dihydrofolate reductase-based protein complementarity analysis to identify essential interaction regions and key residues. The results are found to be highly consistent with an α/β-type complex structure predicted by AlphaFold2 (AF2). We then design mutants based on the predicted structure using a deep learning protein sequence design method. The solved crystal structure of one mutant presents the same core structure as predicted by AF2. Further computational prediction and experimental assessment indicate that the well-defined core structure is conserved across complexes of 4.1G CTD with other potential targets. Thus, we reveal that an intrinsically disordered protein interaction domain uses an α/β-type structure module formed through synergistic folding to recognize broad IDP targets. Moreover, we show that computational prediction and experiment can be jointly applied to segregate true IDP regions from the core structural domains of IDP-IDP complexes and to uncover the structure-dependent mechanisms of some otherwise elusive IDP-IDP interactions. PubMed: 37722056DOI: 10.1073/pnas.2305603120 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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