6x2m: Difference between revisions
New page: '''Unreleased structure''' The entry 6x2m is ON HOLD Authors: Baumhardt, J.M. Description: Crystal Structure of CRM1-Ran-RanBP1 with humanized NES groove [[Category: Unreleased Structu... |
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The | ==Crystal Structure of unliganded CRM1-Ran-RanBP1== | ||
<StructureSection load='6x2m' size='340' side='right'caption='[[6x2m]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6x2m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X2M FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.351Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=6x2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x2m OCA], [https://pdbe.org/6x2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x2m RCSB], [https://www.ebi.ac.uk/pdbsum/6x2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x2m ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/RAN_HUMAN RAN_HUMAN] GTP-binding protein involved in nucleocytoplasmic transport. Required for the import of protein into the nucleus and also for RNA export. Involved in chromatin condensation and control of cell cycle (By similarity). The complex with BIRC5/ survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2.<ref>PMID:10400640</ref> <ref>PMID:8692944</ref> <ref>PMID:18591255</ref> <ref>PMID:18617507</ref> Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.<ref>PMID:10400640</ref> <ref>PMID:8692944</ref> <ref>PMID:18591255</ref> <ref>PMID:18617507</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The E571K mutation of CRM1 is highly prevalent in some cancers, but its mechanism of tumorigenesis is unclear. Glu571 of CRM1 is located in its NES-binding groove, suggesting binding of select NESs may be altered. We generated HEK-293 cells with either monoallelic CRM1WT/E571K or biallelic CRM1E571K/E571K using CRISPR/Cas9. We also combined analysis of binding affinities and structures of 27 diverse NESs for wild-type and E571K CRM1 with structure-based bioinformatics. While most NESs bind the two CRM1 similarly, NESs from Mek1, eIF4E-transporter and RPS2 showed >10-fold affinity differences. These NESs have multiple charged side chains binding close to CRM1 position 571, but this feature alone was not sufficient to predict different binding to CRM1(E571K). Consistent with eIF4E-transporterNES binding weaker to CRM1(E571K), eIF4E-transporter was mislocalized in tumor cells carrying CRM1(E571K). This serves as proof of concept that understanding how CRM1(E571K) affects NES-binding provides a platform for identifying cargos that are mislocalized in cancer upon CRM1 mutation. Lastly, we showed that large affinity changes seen with some NES peptides (of Mek1 and RPS2) do not always translate to the full-length cargos suggesting limitations with current NES prediction methods. Therefore, comprehensive studies like ours are imperative to identify CRM1 cargos with real pathogenic potential. | |||
Recognition of nuclear export signals by CRM1 carrying the oncogenic E571K mutation.,Baumhardt JM, Walker JS, Lee Y, Shakya B, Brautigam CA, Lapalombella R, Grishin N, Chook YM Mol Biol Cell. 2020 Jun 10:mbcE20040233. doi: 10.1091/mbc.E20-04-0233. PMID:32520643<ref>PMID:32520643</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Baumhardt | <div class="pdbe-citations 6x2m" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Exportin 3D structures|Exportin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Saccharomyces cerevisiae]] | |||
[[Category: Baumhardt JM]] |
Latest revision as of 17:41, 18 October 2023
Crystal Structure of unliganded CRM1-Ran-RanBP1Crystal Structure of unliganded CRM1-Ran-RanBP1
Structural highlights
FunctionRAN_HUMAN GTP-binding protein involved in nucleocytoplasmic transport. Required for the import of protein into the nucleus and also for RNA export. Involved in chromatin condensation and control of cell cycle (By similarity). The complex with BIRC5/ survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2.[1] [2] [3] [4] Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.[5] [6] [7] [8] Publication Abstract from PubMedThe E571K mutation of CRM1 is highly prevalent in some cancers, but its mechanism of tumorigenesis is unclear. Glu571 of CRM1 is located in its NES-binding groove, suggesting binding of select NESs may be altered. We generated HEK-293 cells with either monoallelic CRM1WT/E571K or biallelic CRM1E571K/E571K using CRISPR/Cas9. We also combined analysis of binding affinities and structures of 27 diverse NESs for wild-type and E571K CRM1 with structure-based bioinformatics. While most NESs bind the two CRM1 similarly, NESs from Mek1, eIF4E-transporter and RPS2 showed >10-fold affinity differences. These NESs have multiple charged side chains binding close to CRM1 position 571, but this feature alone was not sufficient to predict different binding to CRM1(E571K). Consistent with eIF4E-transporterNES binding weaker to CRM1(E571K), eIF4E-transporter was mislocalized in tumor cells carrying CRM1(E571K). This serves as proof of concept that understanding how CRM1(E571K) affects NES-binding provides a platform for identifying cargos that are mislocalized in cancer upon CRM1 mutation. Lastly, we showed that large affinity changes seen with some NES peptides (of Mek1 and RPS2) do not always translate to the full-length cargos suggesting limitations with current NES prediction methods. Therefore, comprehensive studies like ours are imperative to identify CRM1 cargos with real pathogenic potential. Recognition of nuclear export signals by CRM1 carrying the oncogenic E571K mutation.,Baumhardt JM, Walker JS, Lee Y, Shakya B, Brautigam CA, Lapalombella R, Grishin N, Chook YM Mol Biol Cell. 2020 Jun 10:mbcE20040233. doi: 10.1091/mbc.E20-04-0233. PMID:32520643[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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