6wgh
From Proteopedia
(Difference between revisions)
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==Crystal structure of GDP-bound NRAS with ten residues long internal tandem duplication in the switch II region== | ==Crystal structure of GDP-bound NRAS with ten residues long internal tandem duplication in the switch II region== | ||
| - | <StructureSection load='6wgh' size='340' side='right'caption='[[6wgh]]' scene=''> | + | <StructureSection load='6wgh' size='340' side='right'caption='[[6wgh]], [[Resolution|resolution]] 1.65Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WGH OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WGH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6wgh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WGH OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WGH FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6wgh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wgh OCA], [http://pdbe.org/6wgh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wgh RCSB], [http://www.ebi.ac.uk/pdbsum/6wgh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wgh ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6pq3|6pq3]]</td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NRAS, HRAS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6wgh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wgh OCA], [http://pdbe.org/6wgh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wgh RCSB], [http://www.ebi.ac.uk/pdbsum/6wgh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wgh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/RASN_HUMAN RASN_HUMAN]] Defects in NRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:[http://omim.org/entry/607785 607785]]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:[http://omim.org/entry/613224 613224]]. A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.<ref>PMID:19966803</ref> Defects in NRAS are the cause of autoimmune lymphoproliferative syndrome type 4 (ALPS4) [MIM:[http://omim.org/entry/614470 614470]]. A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies.<ref>PMID:17517660</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/RASN_HUMAN RASN_HUMAN]] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The oncogene RAS is one of the most widely studied proteins in cancer biology, and mutant-active RAS is a driver in many types of solid tumors and hematological malignancies. Yet the biological effects of different RAS mutations and the tissue-specific clinical implications are complex and nuanced. Here, we identified an internal tandem duplication (ITD) in the switch II domain of NRAS from a patient with extremely aggressive colorectal carcinoma. Results of whole-exome DNA sequencing of primary and metastatic tumors indicated that this mutation was present in all analyzed metastases and excluded the presence of any other clear oncogenic driver mutations. Biochemical analysis revealed increased interaction of the RAS ITD with Raf proto-oncogene Ser/Thr kinase (RAF), leading to increased phosphorylation of downstream MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK). The ITD prevented interaction with neurofibromin 1 (NF1)-GTPase-activating protein (GAP), providing a mechanism for sustained activity of the RAS ITD protein. We present the first crystal structures of NRAS and KRAS ITD at 1.65-1.75 A resolutions, respectively, providing insight into the physical interactions of this unique class of RAS variants with its regulatory and effector proteins. Our in-depth bedside-to-bench analysis uncovers the molecular mechanism underlying a case of highly aggressive colorectal cancer and illustrates the importance of robust biochemical and biophysical approaches in the implementation of individualized medicine. | ||
| + | |||
| + | RAS internal tandem duplication disrupts GTPase-activating protein (GAP) binding to activate oncogenic signaling.,Nelson AC, Turbyville TJ, Dharmaiah S, Rigby M, Yang R, Wang TY, Columbus J, Stephens R, Taylor T, Sciacca D, Onsongo G, Sarver A, Subramanian S, Nissley DV, Simanshu DK, Lou E J Biol Chem. 2020 May 11. pii: RA119.011080. doi: 10.1074/jbc.RA119.011080. PMID:32393580<ref>PMID:32393580</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6wgh" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Dharmaiah S]] | + | [[Category: Dharmaiah, S]] |
| - | [[Category: Simanshu | + | [[Category: Simanshu, D K]] |
| + | [[Category: Gdp]] | ||
| + | [[Category: Internal tandem duplication]] | ||
| + | [[Category: Itd]] | ||
| + | [[Category: Mg]] | ||
| + | [[Category: N-ra]] | ||
| + | [[Category: Nra]] | ||
| + | [[Category: Oncoprotein]] | ||
| + | [[Category: Ra]] | ||
Revision as of 07:42, 27 May 2020
Crystal structure of GDP-bound NRAS with ten residues long internal tandem duplication in the switch II region
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Categories: Human | Large Structures | Dharmaiah, S | Simanshu, D K | Gdp | Internal tandem duplication | Itd | Mg | N-ra | Nra | Oncoprotein | Ra
