7KSP

Crystal structure of hSAMD9_DBD with DNA

Summary for 7KSP

• Entry DOI: 10.2210/pdb7ksp/pdb
• Descriptor: Sterile alpha motif domain-containing protein 9, DNA, ... (4 entities in total)
• Functional Keywords: samd9, alba domain, dna binding, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 67016.52

Authors

Peng, S.,Pathak, P.,Xiang, Y.,Deng, J. (deposition date: 2020-11-23, release date: 2022-01-05, Last modification date: 2024-05-22)

Primary citation

Peng, S.,Meng, X.,Zhang, F.,Pathak, P.K.,Chaturvedi, J.,Coronado, J.,Morales, M.,Mao, Y.,Qian, S.B.,Deng, J.,Xiang, Y.
Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L.
Proc.Natl.Acad.Sci.USA, 119:-, 2022

PubMed Abstract: SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases.

PubMed: 35046037
DOI: 10.1073/pnas.2116550119

Experimental method

X-RAY DIFFRACTION (2.8 Å)