4MNE
Crystal structure of the BRAF:MEK1 complex
Summary for 4MNE
| Entry DOI | 10.2210/pdb4mne/pdb |
| Related | 2Y4I 4MNF |
| Descriptor | Dual specificity mitogen-activated protein kinase kinase 1, Serine/threonine-protein kinase B-raf, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (7 entities in total) |
| Functional Keywords | raf, mapk, kinase domain, atp-binding, erk, ras, pak, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) More |
| Cellular location | Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: Q02750 Nucleus (By similarity): P15056 |
| Total number of polymer chains | 8 |
| Total formula weight | 297709.25 |
| Authors | Sudhamsu, J.,Haling, J.R.,Morales, T.,Brandhuber, B.,Hymowitz, S.G. (deposition date: 2013-09-10, release date: 2014-06-18, Last modification date: 2023-09-20) |
| Primary citation | Haling, J.R.,Sudhamsu, J.,Yen, I.,Sideris, S.,Sandoval, W.,Phung, W.,Bravo, B.J.,Giannetti, A.M.,Peck, A.,Masselot, A.,Morales, T.,Smith, D.,Brandhuber, B.J.,Hymowitz, S.G.,Malek, S. Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling. Cancer Cell, 26:402-413, 2014 Cited by PubMed Abstract: Numerous oncogenic mutations occur within the BRAF kinase domain (BRAF(KD)). Here we show that stable BRAF-MEK1 complexes are enriched in BRAF(WT) and KRAS mutant (MT) cells but not in BRAF(MT) cells. The crystal structure of the BRAF(KD) in a complex with MEK1 reveals a face-to-face dimer sensitive to MEK1 phosphorylation but insensitive to BRAF dimerization. Structure-guided studies reveal that oncogenic BRAF mutations function by bypassing the requirement for BRAF dimerization for activity or weakening the interaction with MEK1. Finally, we show that conformation-specific BRAF inhibitors can sequester a dormant BRAF-MEK1 complex resulting in pathway inhibition. Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK. PubMed: 25155755DOI: 10.1016/j.ccr.2014.07.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8483 Å) |
Structure validation
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