7pgt: Difference between revisions

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<StructureSection load='7pgt' size='340' side='right'caption='[[7pgt]], [[Resolution|resolution]] 4.80&Aring;' scene=''>
<StructureSection load='7pgt' size='340' side='right'caption='[[7pgt]], [[Resolution|resolution]] 4.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7pgt]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PGT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PGT FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PGT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PGT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7pgt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pgt OCA], [https://pdbe.org/7pgt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pgt RCSB], [https://www.ebi.ac.uk/pdbsum/7pgt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pgt ProSAT]</span></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=7pgt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pgt OCA], [https://pdbe.org/7pgt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pgt RCSB], [https://www.ebi.ac.uk/pdbsum/7pgt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pgt ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/NF1_HUMAN NF1_HUMAN]] Defects in NF1 are the cause of neurofibromatosis type 1 (NF1) [MIM:[https://omim.org/entry/162200 162200]]; also known as von Recklinghausen syndrome. A disease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors.<ref>PMID:2114220</ref> <ref>PMID:1302608</ref> <ref>PMID:7981679</ref> <ref>PMID:8081387</ref> <ref>PMID:8544190</ref> <ref>PMID:8834249</ref> <ref>PMID:8807336</ref> <ref>PMID:9003501</ref> <ref>PMID:9150739</ref> <ref>PMID:9101300</ref> <ref>PMID:9298829</ref> <ref>PMID:9668168</ref> <ref>PMID:10336779</ref> <ref>PMID:11258625</ref> <ref>PMID:10220149</ref> <ref>PMID:10712197</ref> <ref>PMID:10607834</ref> <ref>PMID:10980545</ref> <ref>PMID:11735023</ref> <ref>PMID:11857752</ref> <ref>PMID:12522551</ref> <ref>PMID:12552569</ref> <ref>PMID:12746402</ref> <ref>PMID:15523642</ref> <ref>PMID:15146469</ref> <ref>PMID:15060124</ref> <ref>PMID:15520408</ref> <ref>PMID:15948193</ref> <ref>PMID:21838856</ref>  Defects in NF1 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:[https://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. Germline mutations of NF1 account for the association of JMML with type 1 neurofibromatosis (NF1).  Defects in NF1 are the cause of Watson syndrome (WS) [MIM:[https://omim.org/entry/193520 193520]]. WS is characterized by the presence of pulmonary stenosis, cafe-au-lait spots, and mental retardation. WS is considered as an atypical form of NF1.  Defects in NF1 are a cause of familial spinal neurofibromatosis (FSNF) [MIM:[https://omim.org/entry/162210 162210]]. Familial spinal NF is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors.<ref>PMID:11704931</ref>  Defects in NF1 are a cause of neurofibromatosis-Noonan syndrome (NFNS) [MIM:[https://omim.org/entry/601321 601321]]. NFNS is characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis.<ref>PMID:12707950</ref> <ref>PMID:16380919</ref> <ref>PMID:19845691</ref>  Defects in NF1 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]].
== Function ==
[[https://www.uniprot.org/uniprot/NF1_HUMAN NF1_HUMAN]] Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity.<ref>PMID:2121371</ref> 
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 7pgt" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 7pgt" style="background-color:#fffaf0;"></div>
==See Also==
*[[Neurofibromin|Neurofibromin]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Baradaran, R]]
[[Category: Baradaran R]]
[[Category: Carroni, M]]
[[Category: Carroni M]]
[[Category: Naschberger, A]]
[[Category: Naschberger A]]
[[Category: Rupp, B]]
[[Category: Rupp B]]
[[Category: Cancer]]
[[Category: Gap]]
[[Category: Neurofibromatosis type 1]]
[[Category: Neurofibromin]]
[[Category: Ra]]
[[Category: Signaling protein]]

Latest revision as of 15:33, 17 July 2024

The structure of human neurofibromin isoform 2 in opened conformation.The structure of human neurofibromin isoform 2 in opened conformation.

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 4.8Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1)(1,2). As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.3 A. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing(3) isoform 2 in a closed, self-inhibited, Zn-stabilized state and an open state. In the closed conformation, HEAT/ARM core domains shield the GTPase-activating protein-related domain (GRD) so that Ras binding is sterically inhibited. In a distinctly different, open conformation of one protomer, a large-scale movement of the GRD occurs, which is necessary to access Ras, whereas Sec14-PH reorients to allow interaction with the cellular membrane(4). Zn incubation of Nf1 leads to reduced Ras-GAP activity with both protomers in the self-inhibited, closed conformation stabilized by a Zn binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker. The transition between closed, self-inhibited states of Nf1 and open states provides guidance for targeted studies deciphering the complex molecular mechanism behind the widespread neurofibromatosis syndrome and Nf1 dysfunction in carcinogenesis.

The structure of neurofibromin isoform 2 reveals different functional states.,Naschberger A, Baradaran R, Rupp B, Carroni M Nature. 2021 Nov;599(7884):315-319. doi: 10.1038/s41586-021-04024-x. Epub 2021, Oct 27. PMID:34707296[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Naschberger A, Baradaran R, Rupp B, Carroni M. The structure of neurofibromin isoform 2 reveals different functional states. Nature. 2021 Nov;599(7884):315-319. doi: 10.1038/s41586-021-04024-x. Epub 2021, Oct 27. PMID:34707296 doi:http://dx.doi.org/10.1038/s41586-021-04024-x

7pgt, resolution 4.80Å

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OCA
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