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- EMDB-70500: Cryo-EM structure of bovine phosphodiesterase 6 bound to CB-5083 -

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Basic information

Entry
Database: EMDB / ID: EMD-70500
TitleCryo-EM structure of bovine phosphodiesterase 6 bound to CB-5083
Map data
Sample
  • Complex: phosphodiesterase 6 complex
    • Protein or peptide: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha
    • Protein or peptide: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta
    • Protein or peptide: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: MAGNESIUM ION
  • Ligand: 1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide
KeywordsGAF domain / phosphohydrolase / G protein-coupled receptor signaling / SIGNALING PROTEIN / CB-5083
Function / homology
Function and homology information


3',5'-cyclic-GMP phosphodiesterase / Inactivation, recovery and regulation of the phototransduction cascade / Activation of the phototransduction cascade / positive regulation of G protein-coupled receptor signaling pathway / Ca2+ pathway / photoreceptor outer segment membrane / entrainment of circadian clock by photoperiod / positive regulation of epidermal growth factor receptor signaling pathway / retina development in camera-type eye / cGMP binding ...3',5'-cyclic-GMP phosphodiesterase / Inactivation, recovery and regulation of the phototransduction cascade / Activation of the phototransduction cascade / positive regulation of G protein-coupled receptor signaling pathway / Ca2+ pathway / photoreceptor outer segment membrane / entrainment of circadian clock by photoperiod / positive regulation of epidermal growth factor receptor signaling pathway / retina development in camera-type eye / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / photoreceptor outer segment / negative regulation of cAMP/PKA signal transduction / visual perception / enzyme inhibitor activity / photoreceptor disc membrane / molecular adaptor activity / signal transduction / zinc ion binding / metal ion binding
Similarity search - Function
Retinal cGMP phosphodiesterase, gamma subunit / Retinal cGMP phosphodiesterase, gamma subunit superfamily / Retinal cGMP phosphodiesterase, gamma subunit / GAF domain profile. / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. ...Retinal cGMP phosphodiesterase, gamma subunit / Retinal cGMP phosphodiesterase, gamma subunit superfamily / Retinal cGMP phosphodiesterase, gamma subunit / GAF domain profile. / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily
Similarity search - Domain/homology
Rod cGMP 3',5'-cyclic phosphodiesterase subunit gamma / Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha / Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsCrawford J / Munuganti R / Leung C / Singh K / Gates E / Zhu X / Bally M / Dos Santos N / Sharifiaghdam M / Nosrati Z ...Crawford J / Munuganti R / Leung C / Singh K / Gates E / Zhu X / Bally M / Dos Santos N / Sharifiaghdam M / Nosrati Z / Axerio-Cilies P / Berezuk A / Cholak S / Cameron D / Subramaniam S
Funding support Canada, 1 items
OrganizationGrant numberCountry
Canada Excellence Research Chair Award Canada
CitationJournal: IUCrJ / Year: 2026
Title: Cryo-EM-guided subtractive optimization of a novel VCP/p97 inhibitor.
Authors: Jason Crawford / Ravi Munuganti / Charles Leung / Kriti Singh / Ellen Gates / Xing Zhu / Marcel Bally / Nancy Dos Santos / Maryam Sharifiaghdam / Zeynab Nosrati / Peter Axerio-Cilies / ...Authors: Jason Crawford / Ravi Munuganti / Charles Leung / Kriti Singh / Ellen Gates / Xing Zhu / Marcel Bally / Nancy Dos Santos / Maryam Sharifiaghdam / Zeynab Nosrati / Peter Axerio-Cilies / Alison M Berezuk / Spencer Cholak / Alan Merk / Dale R Cameron / Sriram Subramaniam /
Abstract: We report the cryo-EM structure-guided discovery of GND-135, a novel small-molecule inhibitor of the VCP/p97 AAA ATPase that demonstrates efficient inhibition of VCP/p97 in biochemical, cellular, and ...We report the cryo-EM structure-guided discovery of GND-135, a novel small-molecule inhibitor of the VCP/p97 AAA ATPase that demonstrates efficient inhibition of VCP/p97 in biochemical, cellular, and pharmacokinetic assays and in a tumor efficacy mouse model of acute myeloid leukemia. Our approach overcomes the liability in the clinical-stage compound CB-5083 where Phase I studies showed off-target activity of CB-5083 for the enzyme PDE6. From the cryo-EM structural analysis of CB-5083 bound to PDE6 and VCP/p97, we identified critical ligand/protein interactions in both proteins and rationally designed a small molecule that retains key interactions necessary for VCP/p97 inhibition while eliminating PDE6 off-target activity. We refer to this approach as `subtractive optimization' because we are leveraging our ability to determine both on-target and off-target cryo-EM structures to guide the medicinal chemistry campaign to enable more targeted compound design. While this strategy is not possible in all cases, the use of cryo-EM to tune on-site binding while eliminating off-target binding could be a generally applicable strategy for informing molecular design and accelerating small-molecule drug discovery.
History
DepositionMay 5, 2025-
Header (metadata) releaseMay 27, 2026-
Map releaseMay 27, 2026-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70500.png

Downloads & links

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Map

FileDownload / File: emd_70500.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 320 pix.
= 332.8 Å		1.04 Å/pix.
x 320 pix.
= 332.8 Å		1.04 Å/pix.
x 320 pix.
= 332.8 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.0678
Minimum - Maximum-0.38646185 - 0.8227355
Average (Standard dev.)-0.00038075182 (±0.01830108)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 332.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_70500_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_70500_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : phosphodiesterase 6 complex

EntireName: phosphodiesterase 6 complex
Components
  • Complex: phosphodiesterase 6 complex
    • Protein or peptide: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha
    • Protein or peptide: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta
    • Protein or peptide: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: MAGNESIUM ION
  • Ligand: 1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide

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Supramolecule #1: phosphodiesterase 6 complex

SupramoleculeName: phosphodiesterase 6 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Bos taurus (domestic cattle)

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Macromolecule #1: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha

MacromoleculeName: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: 3',5'-cyclic-GMP phosphodiesterase
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 99.461789 KDa
Recombinant expressionOrganism: Bos taurus (domestic cattle)
SequenceString: MGEVTAEEVE KFLDSNVSFA KQYYNLRYRA KVISDLLGPR EAAVDFSNYH ALNSVEESEI IFDLLRDFQD NLQAEKCVFN VMKKLCFLL QADRMSLFMY RARNGIAELA TRLFNVHKDA VLEECLVAPD SEIVFPLDMG VVGHVALSKK IVNVPNTEED E HFCDFVDT ...String:
MGEVTAEEVE KFLDSNVSFA KQYYNLRYRA KVISDLLGPR EAAVDFSNYH ALNSVEESEI IFDLLRDFQD NLQAEKCVFN VMKKLCFLL QADRMSLFMY RARNGIAELA TRLFNVHKDA VLEECLVAPD SEIVFPLDMG VVGHVALSKK IVNVPNTEED E HFCDFVDT LTEYQTKNIL ASPIMNGKDV VAIIMVVNKV DGPHFTENDE EILLKYLNFA NLIMKVFHLS YLHNCETRRG QI LLWSGSK VFEELTDIER QFHKALYTVR AFLNCDRYSV GLLDMTKQKE FFDVWPVLMG EAPPYAGPRT PDGREINFYK VID YILHGK EDIKVIPNPP PDHWALVSGL PTYVAQNGLI CNIMNAPSED FFAFQKEPLD ESGWMIKNVL SMPIVNKKEE IVGV ATFYN RKDGKPFDEM DETLMESLTQ FLGWSVLNPD TYELMNKLEN RKDIFQDMVK YHVKCDNEEI QTILKTREVY GKEPW ECEE EELAEILQGE LPDADKYEIN KFHFSDLPLT ELELVKCGIQ MYYELKVVDK FHIPQEALVR FMYSLSKGYR RITYHN WRH GFNVGQTMFS LLVTGKLKRY FTDLEALAMV TAAFCHDIDH RGTNNLYQMK SQNPLAKLHG SSILERHHLE FGKTLLR DE SLNIFQNLNR RQHEHAIHMM DIAIIATDLA LYFKKRTMFQ KIVDQSKTYE TQQEWTQYMM LDQTRKEIVM AMMMTACD L SAITKPWEVQ SKVALLVAAE FWEQGDLERT VLQQNPIPMM DRNKADELPK LQVGFIDFVC TFVYKEFSRF HEEITPMLD GITNNRKEWK ALADEYETKM KGLEEEKQKQ QAANQAAAGS QHGGKQPGGG PASKSCCVQ

UniProtKB: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha

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Macromolecule #2: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta

MacromoleculeName: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: 3',5'-cyclic-GMP phosphodiesterase
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 98.449648 KDa
Recombinant expressionOrganism: Bos taurus (domestic cattle)
SequenceString: MSLSEGQVHR FLDQNPGFAD QYFGRKLSPE DVANACEDGC PEGCTSFREL CQVEESAALF ELVQDMQENV NMERVVFKIL RRLCSILHA DRCSLFMYRQ RNGVAELATR LFSVQPDSVL EDCLVPPDSE IVFPLDIGVV GHVAQTKKMV NVQDVMECPH F SSFADELT ...String:
MSLSEGQVHR FLDQNPGFAD QYFGRKLSPE DVANACEDGC PEGCTSFREL CQVEESAALF ELVQDMQENV NMERVVFKIL RRLCSILHA DRCSLFMYRQ RNGVAELATR LFSVQPDSVL EDCLVPPDSE IVFPLDIGVV GHVAQTKKMV NVQDVMECPH F SSFADELT DYVTRNILAT PIMNGKDVVA VIMAVNKLDG PCFTSEDEDV FLKYLNFGTL NLKIYHLSYL HNCETRRGQV LL WSANKVF EELTDIERQF HKAFYTVRAY LNCDRYSVGL LDMTKEKEFF DVWPVLMGEA QAYSGPRTPD GREILFYKVI DYI LHGKED IKVIPSPPAD HWALASGLPT YVAESGFICN IMNAPADEMF NFQEGPLDDS GWIVKNVLSM PIVNKKEEIV GVAT FYNRK DGKPFDEQDE VLMESLTQFL GWSVLNTDTY DKMNKLENRK DIAQDMVLYH VRCDREEIQL ILPTRERLGK EPADC EEDE LGKILKEVLP GPAKFDIYEF HFSDLECTEL ELVKCGIQMY YELGVVRKFQ IPQEVLVRFL FSVSKGYRRI TYHNWR HGF NVAQTMFTLL MTGKLKSYYT DLEAFAMVTA GLCHDIDHRG TNNLYQMKSQ NPLAKLHGSS ILERHHLEFG KFLLSEE TL NIYQNLNRRQ HEHVIHLMDI AIIATDLALY FKKRTMFQKI VDESKNYEDR KSWVEYLSLE TTRKEIVMAM MMTACDLS A ITKPWEVQSK VALLVAAEFW EQGDLERTVL DQQPIPMMDR NKAAELPKLQ VGFIDFVCTF VYKEFSRFHE EILPMFDRL QNNRKEWKAL ADEYEAKVKA LEEDQKKETT AKKVGTEICN GGPAPRSSTC RIL

UniProtKB: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta

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Macromolecule #3: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiestera...

MacromoleculeName: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma
type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO / EC number: 3',5'-cyclic-GMP phosphodiesterase
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 9.684229 KDa
Recombinant expressionOrganism: Bos taurus (domestic cattle)
SequenceString:
MNLEPPKAEI RSATRVMGGP VTPRKGPPKF KQRQTRQFKS KPPKKGVQGF GDDIPGMEGL GTDITVICPW EAFNHLELHE LAQYGII

UniProtKB: Rod cGMP 3',5'-cyclic phosphodiesterase subunit gamma

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Macromolecule #4: CYCLIC GUANOSINE MONOPHOSPHATE

MacromoleculeName: CYCLIC GUANOSINE MONOPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: PCG
Molecular weightTheoretical: 345.205 Da
Chemical component information

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #7: 1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-...

MacromoleculeName: 1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide
type: ligand / ID: 7 / Number of copies: 2 / Formula: JDP
Molecular weightTheoretical: 413.472 Da
Chemical component information

ChemComp-JDP:
1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 274770
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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