7z38: Difference between revisions

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'''Unreleased structure'''


The entry 7z38 is ON HOLD  until Paper Publication
==Structure of the RAF1-HSP90-CDC37 complex (RHC-I)==
<StructureSection load='7z38' size='340' side='right'caption='[[7z38]], [[Resolution|resolution]] 3.16&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7z38]] is a 4 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=7Z38 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z38 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=7z38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z38 OCA], [https://pdbe.org/7z38 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z38 RCSB], [https://www.ebi.ac.uk/pdbsum/7z38 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z38 ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/HS90B_HUMAN HS90B_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:16478993</ref> <ref>PMID:19696785</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.


Authors:  
Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.,Garcia-Alonso S, Mesa P, Ovejero LP, Aizpurua G, Lechuga CG, Zarzuela E, Santiveri CM, Sanclemente M, Munoz J, Musteanu M, Campos-Olivas R, Martinez-Torrecuadrada J, Barbacid M, Montoya G Mol Cell. 2022 Aug 27. pii: S1097-2765(22)00797-3. doi:, 10.1016/j.molcel.2022.08.012. PMID:36055235<ref>PMID:36055235</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 7z38" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Barbacid M]]
[[Category: Garcia-Alonso S]]
[[Category: Mesa P]]
[[Category: Montoya G]]

Revision as of 09:58, 14 September 2022

Structure of the RAF1-HSP90-CDC37 complex (RHC-I)Structure of the RAF1-HSP90-CDC37 complex (RHC-I)

Structural highlights

7z38 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HS90B_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2]

Publication Abstract from PubMed

RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.

Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.,Garcia-Alonso S, Mesa P, Ovejero LP, Aizpurua G, Lechuga CG, Zarzuela E, Santiveri CM, Sanclemente M, Munoz J, Musteanu M, Campos-Olivas R, Martinez-Torrecuadrada J, Barbacid M, Montoya G Mol Cell. 2022 Aug 27. pii: S1097-2765(22)00797-3. doi:, 10.1016/j.molcel.2022.08.012. PMID:36055235[3]

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

References

  1. ↑ Chadli A, Graham JD, Abel MG, Jackson TA, Gordon DF, Wood WM, Felts SJ, Horwitz KB, Toft D. GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway. Mol Cell Biol. 2006 Mar;26(5):1722-30. PMID:16478993 doi:http://dx.doi.org/26/5/1722
  2. ↑ Retzlaff M, Stahl M, Eberl HC, Lagleder S, Beck J, Kessler H, Buchner J. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 2009 Oct;10(10):1147-53. Epub 2009 Aug 21. PMID:19696785 doi:http://dx.doi.org/embor2009153
  3. ↑ Garcia-Alonso S, Mesa P, Ovejero LP, Aizpurua G, Lechuga CG, Zarzuela E, Santiveri CM, Sanclemente M, Munoz J, Musteanu M, Campos-Olivas R, Martinez-Torrecuadrada J, Barbacid M, Montoya G. Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Mol Cell. 2022 Aug 27. pii: S1097-2765(22)00797-3. doi:, 10.1016/j.molcel.2022.08.012. PMID:36055235 doi:http://dx.doi.org/10.1016/j.molcel.2022.08.012

7z38, resolution 3.16Å

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