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- PDB-8fx4: GC-C-Hsp90-Cdc37 regulatory complex -

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Basic information

Entry
Database: PDB / ID: 8fx4
TitleGC-C-Hsp90-Cdc37 regulatory complex
Components
  • Guanylyl cyclase C
  • Heat shock protein HSP 90-betaHeat shock response
  • Hsp90 co-chaperone Cdc37
KeywordsSIGNALING PROTEIN/CHAPERONE / guanylyl cyclase / receptor / heat shock protein / regulation / SIGNALING PROTEIN / SIGNALING PROTEIN-CHAPERONE complex
Function / homology
Function and homology information


Intestinal infectious diseases / Digestion / receptor guanylyl cyclase signaling pathway / peptide receptor activity / guanylate cyclase / guanylate cyclase activity / cGMP biosynthetic process / adenylate cyclase activity / toxic substance binding / ATP-dependent protein folding chaperone ...Intestinal infectious diseases / Digestion / receptor guanylyl cyclase signaling pathway / peptide receptor activity / guanylate cyclase / guanylate cyclase activity / cGMP biosynthetic process / adenylate cyclase activity / toxic substance binding / ATP-dependent protein folding chaperone / response to toxic substance / melanosome / unfolded protein binding / regulation of cell population proliferation / protein kinase activity / intracellular signal transduction / GTP binding / endoplasmic reticulum membrane / protein kinase binding / ATP hydrolysis activity / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Membrane Guanylate Cyclase receptor GC-C, pseudokinase domain / Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 N terminal kinase binding / Cdc37 ...Membrane Guanylate Cyclase receptor GC-C, pseudokinase domain / Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 N terminal kinase binding / Cdc37 / Cdc37, N-terminal domain / Cdc37 N terminal kinase binding / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Adenylate and Guanylate cyclase catalytic domain / Guanylate cyclase domain profile. / Nucleotide cyclase / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Periplasmic binding protein-like I / Histidine kinase/HSP90-like ATPase superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ribosomal protein S5 domain 2-type fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / Heat shock protein HSP 90-beta / Hsp90 co-chaperone Cdc37 / Guanylyl cyclase C
Similarity search - Component
Biological speciesHomo sapiens (human)
Cricetulus griseus (Chinese hamster)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsCaveney, N.A. / Garcia, K.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Elife / Year: 2023
Title: Structural insight into guanylyl cyclase receptor hijacking of the kinase-Hsp90 regulatory mechanism.
Authors: Nathanael A Caveney / Naotaka Tsutsumi / K Christopher Garcia /
Abstract: Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The structural mechanisms which influence ...Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The structural mechanisms which influence these important physiological processes have yet to be explored. We present the 3.9 Å resolution cryo-EM structure of the human membrane receptor guanylyl cyclase GC-C in complex with Hsp90 and its co-chaperone Cdc37, providing insight into the mechanism of Cdc37 mediated binding of GC-C to the Hsp90 regulatory complex. As a membrane protein and non-kinase client of Hsp90-Cdc37, this work shows the remarkable plasticity of Cdc37 to interact with a broad array of clients with significant sequence variation. Furthermore, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. Given the known druggability of Hsp90, these insights can guide the further development of membrane receptor guanylyl cyclase-targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other membrane receptor guanylyl cyclase-related conditions.
History
DepositionJan 23, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-beta
B: Heat shock protein HSP 90-beta
C: Hsp90 co-chaperone Cdc37
D: Guanylyl cyclase C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)298,3136
Polymers297,2994
Non-polymers1,0142
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Heat shock protein HSP 90-beta / Heat shock response


Mass: 83387.250 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Cricetulus griseus (Chinese hamster) / References: UniProt: A0A8C2MUK8
#2: Protein Hsp90 co-chaperone Cdc37


Mass: 44549.434 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Cricetulus griseus (Chinese hamster) / References: UniProt: G3H6C5
#3: Protein Guanylyl cyclase C / GC-C / Heat-stable enterotoxin receptor / STA receptor / hSTAR / Intestinal guanylate cyclase


Mass: 85974.727 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GUCY2C, GUC2C, STAR / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P25092, guanylate cyclase
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GC-C-Hsp90-Cdc37 regulatory complex / Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 58.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
Image processing
IDImage recording-ID
11
21
CTF correction
IDEM image processing-IDType
11PHASE FLIPPING AND AMPLITUDE CORRECTION
22PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstruction
IDResolution (Å)Resolution methodNum. of particlesImage processing-IDEntry-IDSymmetry type
13.9FSC 0.143 CUT-OFF16563518FX4POINT
23.9FSC 0.143 CUT-OFF16563518FX4POINT
33.9FSC 0.143 CUT-OFF16563528FX4POINT
43.9FSC 0.143 CUT-OFF16563528FX4POINT
RefinementHighest resolution: 3.9 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00413712
ELECTRON MICROSCOPYf_angle_d0.88118441
ELECTRON MICROSCOPYf_dihedral_angle_d5.3831787
ELECTRON MICROSCOPYf_chiral_restr0.0462030
ELECTRON MICROSCOPYf_plane_restr0.0042349

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