6MBW

Structure of Transcription Factor

Summary for 6MBW

• Entry DOI: 10.2210/pdb6mbw/pdb
• Descriptor: Signal transducer and activator of transcription 5B (2 entities in total)
• Functional Keywords: transcription factor, transcription activator
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 131238.75

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2018-08-30, release date: 2019-06-19, Last modification date: 2023-10-11)

Primary citation

de Araujo, E.D.,Erdogan, F.,Neubauer, H.A.,Meneksedag-Erol, D.,Manaswiyoungkul, P.,Eram, M.S.,Seo, H.S.,Qadree, A.K.,Israelian, J.,Orlova, A.,Suske, T.,Pham, H.T.T.,Boersma, A.,Tangermann, S.,Kenner, L.,Rulicke, T.,Dong, A.,Ravichandran, M.,Brown, P.J.,Audette, G.F.,Rauscher, S.,Dhe-Paganon, S.,Moriggl, R.,Gunning, P.T.
Structural and functional consequences of the STAT5BN642H driver mutation.
Nat Commun, 10:2517-2517, 2019

PubMed Abstract: Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5B, a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5B in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5B-driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5B patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5B crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5B can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5B, conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5B activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.

PubMed: 31175292
DOI: 10.1038/s41467-019-10422-7

Experimental method

X-RAY DIFFRACTION (3.29 Å)