4ELL

Structure of the inactive retinoblastoma protein pocket domain

Summary for 4ELL

• Entry DOI: 10.2210/pdb4ell/pdb
• Related: 4ELJ
• Descriptor: Retinoblastoma-associated protein (2 entities in total)
• Functional Keywords: cyclin fold, tumor suppressor, cell cycle
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P06400
• Total number of polymer chains: 2
• Total formula weight: 95349.96

Authors

Burke, J.R.,Rubin, S.M. (deposition date: 2012-04-10, release date: 2012-05-23, Last modification date: 2024-02-28)

Primary citation

Burke, J.R.,Hura, G.L.,Rubin, S.M.
Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control.
Genes Dev., 26:1156-1166, 2012

PubMed Abstract: Cyclin-dependent kinase (Cdk) phosphorylation of the Retinoblastoma protein (Rb) drives cell proliferation through inhibition of Rb complexes with E2F transcription factors and other regulatory proteins. We present the first structures of phosphorylated Rb that reveal the mechanism of its inactivation. S608 phosphorylation orders a flexible "pocket" domain loop such that it mimics and directly blocks E2F transactivation domain (E2F(TD)) binding. T373 phosphorylation induces a global conformational change that associates the pocket and N-terminal domains (RbN). This first multidomain Rb structure demonstrates a novel role for RbN in allosterically inhibiting the E2F(TD)-pocket association and protein binding to the pocket "LxCxE" site. Together, these structures detail the regulatory mechanism for a canonical growth-repressive complex and provide a novel example of how multisite Cdk phosphorylation induces diverse structural changes to influence cell cycle signaling.

PubMed: 22569856
DOI: 10.1101/gad.189837.112

Experimental method

X-RAY DIFFRACTION (1.98 Å)