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- EMDB-29523: GC-C-Hsp90-Cdc37 regulatory complex -

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Basic information

Entry
Database: EMDB / ID: EMD-29523
TitleGC-C-Hsp90-Cdc37 regulatory complex
Map datasharpened map
Sample
  • Complex: GC-C-Hsp90-Cdc37 regulatory complex
    • Protein or peptide: Heat shock protein HSP 90-betaHeat shock response
    • Protein or peptide: Hsp90 co-chaperone Cdc37
    • Protein or peptide: Guanylyl cyclase C
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
Keywordsguanylyl 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
Heat shock protein HSP 90-beta / Hsp90 co-chaperone Cdc37 / Guanylyl cyclase C
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsCaveney NA / Garcia KC
Funding support United States, 1 items
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, 2023-
Header (metadata) releaseJul 12, 2023-
Map releaseJul 12, 2023-
UpdateAug 23, 2023-
Current statusAug 23, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29523.png

Downloads & links

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Map

FileDownload / File: emd_29523.map.gz / Format: CCP4 / Size: 28.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.36256 Å
Density
Contour LevelBy AUTHOR: 0.175
Minimum - Maximum-0.0218821 - 2.3493292
Average (Standard dev.)0.002146361 (±0.033740845)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions196196196
Spacing196196196
CellA=B=C: 267.0624 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29523_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29523_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_29523_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : GC-C-Hsp90-Cdc37 regulatory complex

EntireName: GC-C-Hsp90-Cdc37 regulatory complex
Components
  • Complex: GC-C-Hsp90-Cdc37 regulatory complex
    • Protein or peptide: Heat shock protein HSP 90-betaHeat shock response
    • Protein or peptide: Hsp90 co-chaperone Cdc37
    • Protein or peptide: Guanylyl cyclase C
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: GC-C-Hsp90-Cdc37 regulatory complex

SupramoleculeName: GC-C-Hsp90-Cdc37 regulatory complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Macromolecule #1: Heat shock protein HSP 90-beta

MacromoleculeName: Heat shock protein HSP 90-beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Molecular weightTheoretical: 83.38725 KDa
SequenceString: MPEEVHHGEE EVETFAFQAE IAQLMSLIIN TFYSNKEIFL RELISNASDA LDKIRYESLT DPSKLDSGKE LKIDIIPNPQ ERTLTLVDT GIGMTKADLI NNLGTIAKSG TKAFMEALQA GADISMIGQF GVGFYSAYLV AEKVVVITKH NDDEQYAWES S AGGSFTVR ...String:
MPEEVHHGEE EVETFAFQAE IAQLMSLIIN TFYSNKEIFL RELISNASDA LDKIRYESLT DPSKLDSGKE LKIDIIPNPQ ERTLTLVDT GIGMTKADLI NNLGTIAKSG TKAFMEALQA GADISMIGQF GVGFYSAYLV AEKVVVITKH NDDEQYAWES S AGGSFTVR ADHGEPIGRG TKVILHLKED QTEYLEERRV KEVVKKHSQF IGYPITLYLE KEREKEISDD EAEEEKGEKE EE DKDDEEK PKIEDVGSDE EDDSGKDKKK KTKKIKEKYI DQEELNKTKP IWTRNPDDIT QEEYGEFYKS LTNDWEDHLA VKH FSVEGQ LEFRALLFIP RRAPFDLFEN KKKKNNIKLY VRRVFIMDSC DELIPEYLNF IRGVVDSEDL PLNISREMLQ QSKI LKVIR KNIVKKCLEL FSELAEDKEN YKKFYEAFSK NLKLGIHEDS TNRRRLSELL RYHTSQSGDE MTSLSEYVSR MKETQ KSIY YITGESKEQV ANSAFVERVR KRGFEVVYMT EPIDEYCVQQ LKEFDGKSLV SVTKEGLELP EDEEEKKKME ESKAKF ENL CKLMKEILDK KVEKVTISNR LVSSPCCIVT STYGWTANME RIMKAQALRD NSTMGYMMAK KHLEINPDHP IVETLRQ KA EADKNDKAVK DLVVLLFETA LLSSGFSLED PQTHSNRIYR MIKLGLGIDE DEVTAEEPSA AVPDEIPPLE GDEDASRM E EVD

UniProtKB: Heat shock protein HSP 90-beta

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Macromolecule #2: Hsp90 co-chaperone Cdc37

MacromoleculeName: Hsp90 co-chaperone Cdc37 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Molecular weightTheoretical: 44.549434 KDa
SequenceString: MVDYSVWDHI EVSDDEDETH PNIDTASLFR WRHQARVERM EQFQKEKEEL DRGCRECKRK VAECQRKLRE LEVAEGGGQV ELERLRAEA QQLRKEERSW EQKLEDMRKK EKSMPWNVDT LSKDGFSKSI VNIKPEKAEE DSEEAREQKH KTFVEKYEKQ I KHFGMLHR ...String:
MVDYSVWDHI EVSDDEDETH PNIDTASLFR WRHQARVERM EQFQKEKEEL DRGCRECKRK VAECQRKLRE LEVAEGGGQV ELERLRAEA QQLRKEERSW EQKLEDMRKK EKSMPWNVDT LSKDGFSKSI VNIKPEKAEE DSEEAREQKH KTFVEKYEKQ I KHFGMLHR WDDSQKYLSD NVHLVCEETA NYLVIWCIDL EVEEKCALME QVAHQTMVMQ FILELAKSLK VDPRACFRQF FT KIKTADQ QYMEGFKYEL EAFKERVRGR AKLRIEKAMK EYEEEERKKR LGPGGLDPVE VYESLPEELQ KCFDVKDVQM LQD AISKMD PTDAKFHMQR CIDSGLWVPN SKSGEAKEGE EAGPGDPLLE AVPKAGNEKD VSA

UniProtKB: Hsp90 co-chaperone Cdc37

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Macromolecule #3: Guanylyl cyclase C

MacromoleculeName: Guanylyl cyclase C / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: guanylate cyclase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85.974727 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DYKDDDDKGS LEVLFQGPGR MKQLEDKVEE LLSKNYHLEN EVARLKKLVG ERKLPNDITG RGPQILMIAV FTLTGAVVLL LLVALLMLR KYRKDYELRQ KKWSHIPPEN IFPLETNETN HVSLKIDDDK RRDTIQRLRQ CKYDKKRVIL KDLKHNDGNF T EKQKIELN ...String:
DYKDDDDKGS LEVLFQGPGR MKQLEDKVEE LLSKNYHLEN EVARLKKLVG ERKLPNDITG RGPQILMIAV FTLTGAVVLL LLVALLMLR KYRKDYELRQ KKWSHIPPEN IFPLETNETN HVSLKIDDDK RRDTIQRLRQ CKYDKKRVIL KDLKHNDGNF T EKQKIELN KLLQIDYYNL TKFYGTVKLD TMIFGVIEYC ERGSLREVLN DTISYPDGTF MDWEFKISVL YDIAKGMSYL HS SKTEVHG RLKSTNCVVD SRMVVKITDF GCNSILPPKK DLWTAPEHLR QANISQKGDV YSYGIIAQEI ILRKETFYTL SCR DRNEKI FRVENSNGMK PFRPDLFLET AEEKELEVYL LVKNCWEEDP EKRPDFKKIE TTLAKIFGLF HDQKNESYMD TLIR RLQLY SRNLEHLVEE RTQLYKAERD RADRLNFMLL PRLVVKSLKE KGFVEPELYE EVTIYFSDIV GFTTICKYST PMEVV DMLN DIYKSFDHIV DHHDVYKVET IGDAYMVASG LPKRNGNRHA IDIAKMALEI LSFMGTFELE HLPGLPIWIR IGVHSG PCA AGVVGIKMPR YCLFGDTVNT ASRMESTGLP LRIHVSGSTI AILKRTECQF LYEVRGETYL KGRGNETTYW LTGMKDQ KF NLPTPPTVEN QQRLQAEFSD MIANSLQKRQ AAGIRSQKPR RVASYKKGTL EYLQLNTTDK ESTYFAAALE VLFQGPGA A EDQVDPRLID GKHHHHHHHH

UniProtKB: Guanylyl cyclase C

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Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.8 e/Å2

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Image processing #1

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 165635
Image processing ID1
FSC plot (resolution estimation)

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Image processing #2

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 165635
Image processing ID2
FSC plot (resolution estimation)

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