{"entry": {"accession": "MF7000827", "general": {"name": "DcpS with inhibitor DG156844", "pdb_id": "3bl7", "exp_method": "X-ray", "resolution": "2.31", "assembly": "Homodimer", "source_organism": "Homo sapiens", "publication": {"pmid": "18839960", "authors": "Singh J, Salcius M, Liu SW, Staker BL, Mishra R, Thurmond J, Michaud G, Mattoon DR, Printen J, Christensen J, Bjornsson JM, Pollok BA, Kiledjian M, Stewart L, Jarecki J, Gurney ME", "title": "DcpS as a therapeutic target for spinal muscular atrophy.", "journal": "ACS Chem. Biol.", "year": "2008", "issue": "11", "volume": "3", "pages": "711-22", "abstract": "Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene,SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by 2-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-substituted quinazoline probe, we identified the scavenger decapping enzyme, DcpS, as a potential binder. We show that the C5-substituted quinazolines potently inhibit DcpS decapping activity and that the potency of inhibition correlates with potency forSMN2 promoter induction. Binding of C5-substituted quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m(7)GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule."}}, "function": {"molecular_function": {"go": [{"accession": "GO:0140932", "name": "5'-(N(7)-methyl 5'-triphosphoguanosine)-[mRNA] diphosphatase activity"}, {"accession": "GO:0042802", "name": "identical protein binding"}, {"accession": "GO:0000340", "name": "RNA 7-methylguanosine cap binding"}, {"accession": "GO:0004532", "name": "RNA exonuclease activity"}]}, "cellular_component": {"go": [{"accession": "GO:0005737", "name": "cytoplasm"}, {"accession": "GO:0005829", "name": "cytosol"}, {"accession": "GO:0005739", "name": "mitochondrion"}, {"accession": "GO:0005654", "name": "nucleoplasm"}, {"accession": "GO:0005634", "name": "nucleus"}, {"accession": "GO:0000932", "name": "P-body"}]}, "biological_process": {"go": [{"accession": "GO:0000290", "name": "deadenylation-dependent decapping of nuclear-transcribed mRNA"}, {"accession": "GO:0045292", "name": "mRNA cis splicing, via spliceosome"}, {"accession": "GO:0110156", "name": "mRNA methylguanosine-cap decapping"}, {"accession": "GO:0000288", "name": "nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay"}]}}, "macromolecules": {"general": {"nr_of_chains": "2", "nr_of_unique_protein_segments": "1", "class": "Homooligomeric enzymes", "subclass": "Homodimeric enzymes", "note": "All chains according to the most probable oligomerization state stored in PDBe were considered."}, "chain": [{"id": "A", "name": "m7GpppX diphosphatase", "source_organism": "Homo sapiens", "uniprot": {"id": "Q96C86", "start": "42", "end": "334", "coverage": "86%", "sequence": "MADAAPQLGKRKRELDVEEAHAASTEEKEAGVGNGTCAPVRLPFSGFRLQKVLRESARDKIIFLHGKVNEASGDGDGEDAVVILEKTPFQVEQVAQLLTGSPELQLQFSNDIYSTYHLFPPRQLNDVKTTVVYPATEKHLQKYLRQDLRLIRETGDDYRNITLPHLESQSLSIQWVYNILDKKAEADRIVFENPDPSDGFVLIPDLKWNQQQLDDLYLIAICHRRGIRSLRDLTPEHLPLLRNILHQGQEAILQRYRMKGDHLRVYLHYLPSYYHLHVHFTALGFEAPGSGVERAHLLAEVIENLECDPRHYQQRTLTFALRADDPLLKLLQEAQQS", "length": "337"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "54", "region_end": "63"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "85", "region_end": "89"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "100", "region_end": "107"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "118", "region_end": "125"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "125", "region_end": "132"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "137", "region_end": "145"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "149", "region_end": "153"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "176", "region_end": "179"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "193", "region_end": "197"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "198", "region_end": "200"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "201", "region_end": "221"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "223", "region_end": "225"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "262", "region_end": "272"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "274", "region_end": "279"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "289", "region_end": "297"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "12", "region_end": "20"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "25", "region_end": "31"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "43", "region_end": "50"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "67", "region_end": "74"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "77", "region_end": "83"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "91", "region_end": "96"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "112", "region_end": "117"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "155", "region_end": "157"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "164", "region_end": "168"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "181", "region_end": "186"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "227", "region_end": "232"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "241", "region_end": "246"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "259", "region_end": "261"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "281", "region_end": "286"}, {"region_type": "pfam", "region_id": "PF11969", "region_name": "Scavenger mRNA decapping enzyme C-term binding", "region_start": "174", "region_end": "292"}]}}, {"id": "B", "name": "m7GpppX diphosphatase", "source_organism": "Homo sapiens", "uniprot": {"id": "Q96C86", "start": "40", "end": "336", "coverage": "88%", "sequence": "MADAAPQLGKRKRELDVEEAHAASTEEKEAGVGNGTCAPVRLPFSGFRLQKVLRESARDKIIFLHGKVNEASGDGDGEDAVVILEKTPFQVEQVAQLLTGSPELQLQFSNDIYSTYHLFPPRQLNDVKTTVVYPATEKHLQKYLRQDLRLIRETGDDYRNITLPHLESQSLSIQWVYNILDKKAEADRIVFENPDPSDGFVLIPDLKWNQQQLDDLYLIAICHRRGIRSLRDLTPEHLPLLRNILHQGQEAILQRYRMKGDHLRVYLHYLPSYYHLHVHFTALGFEAPGSGVERAHLLAEVIENLECDPRHYQQRTLTFALRADDPLLKLLQEAQQS", "length": "337"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "54", "region_end": "64"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "85", "region_end": "89"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "100", "region_end": "108"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "118", "region_end": "125"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "125", "region_end": "132"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "137", "region_end": "145"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "193", "region_end": "197"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "198", "region_end": "200"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "201", "region_end": "221"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "223", "region_end": "225"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "262", "region_end": "272"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "274", "region_end": "279"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "289", "region_end": "298"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "12", "region_end": "20"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "25", "region_end": "31"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "43", "region_end": "50"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "68", "region_end": "74"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "77", "region_end": "82"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "91", "region_end": "96"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "112", "region_end": "117"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "155", "region_end": "157"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "164", "region_end": "168"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "181", "region_end": "186"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "227", "region_end": "232"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "241", "region_end": "246"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "259", "region_end": "261"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "281", "region_end": "286"}, {"region_type": "pfam", "region_id": "PF11969", "region_name": "Scavenger mRNA decapping enzyme C-term binding", "region_start": "174", "region_end": "292"}]}}]}, "evidence": {"evidence_level": "Indirect evidence", "evidence_coverage": "Only some parts of the structure participates in mutual synergistic folding.", "sequence_domain": "Scavenger mRNA decapping enzyme (DcpS)", "complex_evidence": "Multidomain structure, where the domain-swapped N-terminal domain is responsible for dimerization. The extensive interface, symmetry, topology, beta sheet augmentation and buried surface area suggest that the N-terminal dimerization domain behaves as a single rigid domain and the monomers would not be stable on their own. Gel-filtration chromatography also suggested a dimeric form (PMID:15068804).", "chain_evidence": [{"chain_id": "A", "support": "N/A"}, {"chain_id": "B", "support": "N/A"}]}, "related_structures": {"id": ["MF7000822", "MF7000823", "MF7000824", "MF7000825", "MF7000826", "MF7000827", "MF7000828", "MF7000829"]}}}