3pgl

Crystal structure of human small C-terminal domain phosphatase 1 (Scp1) bound to rabeprazole

spinqualitylabelsall models 3pgl, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3pgl is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MG, RZX Related: 3l0b, 3l0c, 3l0y, 2ghq, 2ght, 1t9z Gene: CTDSP1, CTDSP1 or SCP1, NIF3, NLIIF, SCP1 (HUMAN) Activity: Phosphoprotein phosphatase, with EC number 3.1.3.16 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CTDS1_HUMAN] Preferentially catalyzes the dephosphorylation of 'Ser-5' within the tandem 7 residues repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation. Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells. Publication Abstract from PubMed The unstructured C-terminal domain (CTD) of eukaryotic RNA polymerase II dynamically regulates the process of transcription by recruiting different factors to nascent mRNA through its multiple phosphorylation patterns. A newly discovered class of phosphatases, the human small C-terminal domain phosphatases (Scp's), specifically dephosphorylates phosphorylated Ser(5) (phospho.Ser(5)) of the tandem heptad repeats of the CTD of RNA polymerase II. Scp's also function as transcription regulators that epigenetically silence the expression of specific neuronal genes, whose inactivation leads to neuronal stem cell differentiation. Small molecule inhibitors of Scp's will be valuable for elucidating their mechanism in nervous system development and can possibly offer new strategies to treat diseases related to neurodegeneration. Despite the difficulty in developing selective inhibitors of protein phosphatases, we have recognized a characteristic hydrophobic binding pocket adjacent to the active site in Scp's that may facilitate selective inhibition. In the present study, we successfully identified the first selective lead compound, rabeprazole, for the Scp/TFIIF-interacting CTD phosphatase (Fcp) family. The high-resolution crystal structure of rabeprazole-bound Scp1 showed that the compound indeed binds to the hydrophobic binding pocket. We further confirmed that rabeprazole only targets Scp's but not its close family members Fcp1 and Dullard or bacteriophage lambda Ser/Thr phosphatase. Such specificity may prove important for In Vivo studies since accidental inhibition of Fcp1 or Dullard would result in cell malfunctions and even cell death. Selective Inactivation of a Human Neuronal Silencing Phosphatase by a Small Molecule Inhibitor.,Zhang M, Cho EJ, Burstein G, Siegel D, Zhang Y ACS Chem Biol. 2011 Feb 24. PMID:21348431 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA