General Information

Database accession: MF7000826

Name: DcpS with inhibitor DG153249

PDB ID: 3bla PDBe

Experimental method: X-ray (2.60 Å)

Assembly: Homodimer

Source organism: Homo sapiens

Primary publication of the structure:

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
DcpS as a therapeutic target for spinal muscular atrophy.
(2008) ACS Chem. Biol. 3: 711-22

PMID: 18839960 PubMed

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 and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function:

5'-(N(7)-methyl 5'-triphosphoguanosine)-[mRNA] diphosphatase activity 5'-(N(7)-methyl 5'-triphosphoguanosine)-[mRNA] diphosphatase activity GeneOntology

identical protein binding identical protein binding GeneOntology

RNA 7-methylguanosine cap binding RNA 7-methylguanosine cap binding GeneOntology

RNA exonuclease activity RNA exonuclease activity GeneOntology

Biological process:

deadenylation-dependent decapping of nuclear-transcribed mRNA deadenylation-dependent decapping of nuclear-transcribed mRNA GeneOntology

mRNA cis splicing, via spliceosome mRNA cis splicing, via spliceosome GeneOntology

mRNA methylguanosine-cap decapping mRNA methylguanosine-cap decapping GeneOntology

nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay GeneOntology

Cellular component:

cytoplasm cytoplasm GeneOntology

cytosol cytosol GeneOntology

mitochondrion mitochondrion GeneOntology

nucleoplasm nucleoplasm GeneOntology

nucleus nucleus GeneOntology

P-body P-body GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 2 distinct polypeptide molecules

Chains: A, B

Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.

Number of unique protein segments: 1


Chain A

Name: m7GpppX diphosphatase

Source organism: Homo sapiens

Length: 337 residues

Sequence:Sequence according to the corresponding UniProt protein segmentMADAAPQLGKRKRELDVEEAHAASTEEKEAGVGNGTCAPVRLPFSGFRLQKVLRESARDKIIFLHGKVNEASGDGDGEDAVVILEKTPFQVEQVAQLLTGSPELQLQFSNDIYSTYHLFPPRQLNDVKTTVVYPATEKHLQKYLRQDLRLIRETGDDYRNITLPHLESQSLSIQWVYNILDKKAEADRIVFENPDPSDGFVLIPDLKWNQQQLDDLYLIAICHRRGIRSLRDLTPEHLPLLRNILHQGQEAILQRYRMKGDHLRVYLHYLPSYYHLHVHFTALGFEAPGSGVERAHLLAEVIENLECDPRHYQQRTLTFALRADDPLLKLLQEAQQS

UniProtKB AC: Q96C86 (positions: 42-334) UniProt

Coverage: 86%

Chain B

Name: m7GpppX diphosphatase

Source organism: Homo sapiens

Length: 337 residues

Sequence:Sequence according to the corresponding UniProt protein segmentMADAAPQLGKRKRELDVEEAHAASTEEKEAGVGNGTCAPVRLPFSGFRLQKVLRESARDKIIFLHGKVNEASGDGDGEDAVVILEKTPFQVEQVAQLLTGSPELQLQFSNDIYSTYHLFPPRQLNDVKTTVVYPATEKHLQKYLRQDLRLIRETGDDYRNITLPHLESQSLSIQWVYNILDKKAEADRIVFENPDPSDGFVLIPDLKWNQQQLDDLYLIAICHRRGIRSLRDLTPEHLPLLRNILHQGQEAILQRYRMKGDHLRVYLHYLPSYYHLHVHFTALGFEAPGSGVERAHLLAEVIENLECDPRHYQQRTLTFALRADDPLLKLLQEAQQS

UniProtKB AC: Q96C86 (positions: 40-336) UniProt

Coverage: 88%

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

Representative domain in related structures: Scavenger mRNA decapping enzyme (DcpS)

Evidence level: Indirect evidence

Evidence coverage: Only some parts of the structure participates in mutual synergistic folding.

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 A:

N/A

Chain B:

N/A

Surface and contacts features:

Related Structure(s) Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap).

There are 8 related structures in the MFIB database:






The molecule viewer shows our modified stucture.

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