View source for 7xw2


==Cryo-EM structure of human DICER-pre-miRNA in a dicing state==
<StructureSection load='7xw2' size='340' side='right'caption='[[7xw2]], [[Resolution|resolution]] 3.04&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xw2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XW2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.04&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7xw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xw2 OCA], [https://pdbe.org/7xw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xw2 RCSB], [https://www.ebi.ac.uk/pdbsum/7xw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xw2 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DICER_HUMAN DICER_HUMAN] Defects in DICER1 are a cause of pleuropulmonary blastoma (PPB) [MIM:[https://omim.org/entry/601200 601200]. PPB is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome. PPBs contain both epithelial and mesenchymal cells. Early in tumorigenesis, cysts form in lung airspaces, and these cysts are lined with benign-appearing epithelium. Mesenchymal cells susceptible to malignant transformation reside within the cyst walls and form a dense 'cambium' layer beneath the epithelial lining. In a subset of patients, overgrowth of the mesenchymal cells produces a sarcoma, a transition that is associated with a poorer prognosis.<ref>PMID:21882293</ref> <ref>PMID:19556464</ref>   Defects in DICER1 are the cause of goiter multinodular type 1 with or without Sertoli-Leydig cell tumors (MNG1) [MIM:[https://omim.org/entry/138800 138800]. A common disorder characterized by nodular overgrowth of the thyroid gland. Some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary.<ref>PMID:21882293</ref> <ref>PMID:21205968</ref>   Note=DICER1 mutations have been found in uterine cervix embryonal rhabdomyosarcoma, primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration and juvenile intestinal polyp (PubMed:21882293). Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in non-epithelial ovarian tumors. These mutations do not abolish DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic (PubMed:22187960).<ref>PMID:21882293</ref> 
== Function ==
[https://www.uniprot.org/uniprot/DICER_HUMAN DICER_HUMAN] Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, EIF2C2/AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Also cleaves double-stranded RNA to produce short interfering RNAs (siRNAs) which target the selective destruction of complementary RNAs.<ref>PMID:15242644</ref> <ref>PMID:16271387</ref> <ref>PMID:16289642</ref> <ref>PMID:16142218</ref> <ref>PMID:16357216</ref> <ref>PMID:15973356</ref> <ref>PMID:16424907</ref> <ref>PMID:17452327</ref> <ref>PMID:18178619</ref> <ref>PMID:19219043</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Dicer has a key role in small RNA biogenesis, processing double-stranded RNAs (dsRNAs)(1,2). Human DICER (hDICER, also known as DICER1) is specialized for cleaving small hairpin structures such as precursor microRNAs (pre-miRNAs) and has limited activity towards long dsRNAs-unlike its homologues in lower eukaryotes and plants, which cleave long dsRNAs. Although the mechanism by which long dsRNAs are cleaved has been well documented, our understanding of pre-miRNA processing is incomplete because structures of hDICER in a catalytic state are lacking. Here we report the cryo-electron microscopy structure of hDICER bound to pre-miRNA in a dicing state and uncover the structural basis of pre-miRNA processing. hDICER undergoes large conformational changes to attain the active state. The helicase domain becomes flexible, which allows the binding of pre-miRNA to the catalytic valley. The double-stranded RNA-binding domain relocates and anchors pre-miRNA in a specific position through both sequence-independent and sequence-specific recognition of the newly identified 'GYM motif'(3). The DICER-specific PAZ helix is also reoriented to accommodate the RNA. Furthermore, our structure identifies a configuration of the 5' end of pre-miRNA inserted into a basic pocket. In this pocket, a group of arginine residues recognize the 5' terminal base (disfavouring guanine) and terminal monophosphate; this explains the specificity of hDICER and how it determines the cleavage site. We identify cancer-associated mutations in the 5' pocket residues that impair miRNA biogenesis. Our study reveals how hDICER recognizes pre-miRNAs with stringent specificity and enables a mechanistic understanding of hDICER-related diseases.

Structure of the human DICER-pre-miRNA complex in a dicing state.,Lee YY, Lee H, Kim H, Kim VN, Roh SH Nature. 2023 Mar;615(7951):331-338. doi: 10.1038/s41586-023-05723-3. Epub 2023 , Feb 22. PMID:36813958<ref>PMID:36813958</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7xw2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lee H]]
[[Category: Roh S-H]]