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- PDB-7q9u: Crystal structure of the high affinity KRas mutant PDE6D complex -

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Basic information

Entry
Database: PDB / ID: 7q9u
TitleCrystal structure of the high affinity KRas mutant PDE6D complex
Components
  • GTPase KRas
  • Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
KeywordsSIGNALING PROTEIN / Cancer / Drug Discovery / Complex
Function / homology
Function and homology information


ARL13B-mediated ciliary trafficking of INPP5E / GTPase inhibitor activity / response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity ...ARL13B-mediated ciliary trafficking of INPP5E / GTPase inhibitor activity / response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / visual perception / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / response to glucocorticoid / cytoplasmic vesicle membrane / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / small GTPase binding / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding
Similarity search - Function
Retinal rod rhodopsin-sensitive cGMP 3', 5'-cyclic phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit superfamily / GMP-PDE, delta subunit / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase ...Retinal rod rhodopsin-sensitive cGMP 3', 5'-cyclic phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit superfamily / GMP-PDE, delta subunit / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Immunoglobulin E-set / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
FARNESYL / GUANOSINE-5'-DIPHOSPHATE / Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.238 Å
AuthorsYelland, T. / Ismail, I.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.
Authors: Yelland, T. / Garcia, E. / Parry, C. / Kowalczyk, D. / Wojnowska, M. / Gohlke, A. / Zalar, M. / Cameron, K. / Goodwin, G. / Yu, Q. / Zhu, P.C. / ElMaghloob, Y. / Pugliese, A. / Archibald, L. ...Authors: Yelland, T. / Garcia, E. / Parry, C. / Kowalczyk, D. / Wojnowska, M. / Gohlke, A. / Zalar, M. / Cameron, K. / Goodwin, G. / Yu, Q. / Zhu, P.C. / ElMaghloob, Y. / Pugliese, A. / Archibald, L. / Jamieson, A. / Chen, Y.X. / McArthur, D. / Bower, J. / Ismail, S.
History
DepositionNov 14, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.0Dec 7, 2022Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_type ...atom_site / atom_type / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly_gen / pdbx_struct_mod_residue / struct_asym / struct_conn / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_alt_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _atom_site.occupancy / _atom_site.type_symbol / _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _entity_poly.nstd_monomer / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_seq_id / _struct_ref.db_code / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_db_isoform / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_end / _struct_ref_seq_dif.details / _struct_ref_seq_dif.pdbx_seq_db_accession_code
Revision 2.1Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_conn
Item: _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: GTPase KRas
BBB: GTPase KRas
DDD: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
CCC: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,92416
Polymers77,0264
Non-polymers1,89812
Water2,738152
1
AAA: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,7223
Polymers21,0721
Non-polymers6502
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,8184
Polymers21,0721
Non-polymers7463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
DDD: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,6614
Polymers17,4411
Non-polymers2203
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
CCC: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,7235
Polymers17,4411
Non-polymers2824
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.086, 57.925, 78.913
Angle α, β, γ (deg.)82.771, 81.709, 68.447
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11Chains AAA BBB
21Chains DDD CCC

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Components

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Protein , 2 types, 4 molecules AAABBBDDDCCC

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 21072.023 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Homo sapiens (human) / References: UniProt: P01116, small monomeric GTPase
#2: Protein Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta / GMP-PDE delta / Protein p17


Mass: 17440.990 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE6D, PDED / Production host: Escherichia coli (E. coli) / References: UniProt: O43924

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Non-polymers , 5 types, 164 molecules

#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-FAR / FARNESYL


Mass: 206.367 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H26
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.88 Å3/Da / Density % sol: 57.24 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Ammonium sulphate, 0.1 M tri sodium citrate pH 5.6, 15 % w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97628 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97628 Å / Relative weight: 1
ReflectionResolution: 2.238→53.706 Å / Num. obs: 37781 / % possible obs: 94.7 % / Redundancy: 1.7 % / CC1/2: 0.995 / Net I/σ(I): 6.1
Reflection shellResolution: 2.24→2.3 Å / Num. unique obs: 2327 / CC1/2: 0.742

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TB5

5tb5


Resolution: 2.238→53.706 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.931 / WRfactor Rfree: 0.276 / WRfactor Rwork: 0.214 / SU B: 8.297 / SU ML: 0.195 / Average fsc free: 0.849 / Average fsc work: 0.8755 / Cross valid method: FREE R-VALUE / ESU R: 0.293 / ESU R Free: 0.232
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2545 1774 4.739 %
Rwork0.1994 35661 -
all0.202 --
obs-37435 93.496 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 46.809 Å2
Baniso -1Baniso -2Baniso -3
1--0.621 Å2-0.994 Å2-0.933 Å2
2--0.469 Å20.805 Å2
3----0.876 Å2
Refinement stepCycle: LAST / Resolution: 2.238→53.706 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5140 0 137 152 5429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0010.0135420
X-RAY DIFFRACTIONr_bond_other_d0.0030.0175076
X-RAY DIFFRACTIONr_angle_refined_deg1.6091.6697287
X-RAY DIFFRACTIONr_angle_other_deg1.3411.59411770
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9815643
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.16822.007304
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.17915996
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9341540
X-RAY DIFFRACTIONr_chiral_restr0.0730.2695
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025955
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021161
X-RAY DIFFRACTIONr_nbd_refined0.20.2872
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1980.24402
X-RAY DIFFRACTIONr_nbtor_refined0.1590.22425
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0830.22393
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1750.2171
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0330.26
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.250.233
X-RAY DIFFRACTIONr_nbd_other0.2480.2147
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2510.218
X-RAY DIFFRACTIONr_mcbond_it3.6764.6812586
X-RAY DIFFRACTIONr_mcbond_other3.6764.6812585
X-RAY DIFFRACTIONr_mcangle_it5.4027.013223
X-RAY DIFFRACTIONr_mcangle_other5.4017.013224
X-RAY DIFFRACTIONr_scbond_it4.5665.2692834
X-RAY DIFFRACTIONr_scbond_other4.5665.2692835
X-RAY DIFFRACTIONr_scangle_it7.0437.6654064
X-RAY DIFFRACTIONr_scangle_other7.0427.6654065
X-RAY DIFFRACTIONr_lrange_it9.08753.1765665
X-RAY DIFFRACTIONr_lrange_other9.08653.1685660
X-RAY DIFFRACTIONr_ncsr_local_group_10.0970.055304
X-RAY DIFFRACTIONr_ncsr_local_group_20.0760.054465
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.238-2.2960.3661000.36320550.36329630.6470.65872.73030.363
2.296-2.3590.381380.33624250.33928680.6930.74489.36540.336
2.359-2.4270.361200.3124730.31228210.770.78491.91780.302
2.427-2.5010.3671230.29724320.327140.7640.80894.14150.289
2.501-2.5830.3421240.28223770.28526230.830.83295.34880.274
2.583-2.6740.3571370.26823010.27225610.7880.85595.19720.258
2.674-2.7740.3151010.23722550.2424740.8590.89195.23040.229
2.774-2.8870.236990.20621420.20823590.9210.93194.99790.201
2.887-3.0150.2561070.20320880.20522910.9140.92595.80970.2
3.015-3.1620.294860.20319970.20621700.8790.91695.99080.207
3.162-3.3320.272860.19619020.220610.8960.92496.4580.203
3.332-3.5340.248840.18818030.1919600.9220.9496.27550.197
3.534-3.7760.257730.18116810.18418280.920.94695.95190.198
3.776-4.0770.213740.16315820.16617130.9390.95296.67250.182
4.077-4.4640.202750.14814820.15115930.9540.96297.74010.171
4.464-4.9870.234550.14113320.14514200.9460.96897.67610.167
4.987-5.750.206560.16211760.16412710.9580.96496.93150.184
5.75-7.0220.257620.1939720.19710500.9310.94798.47620.227
7.022-9.8470.149440.1527590.1528330.9670.96296.39860.191
9.847-53.7060.187300.1994270.1984650.9560.94898.27960.244

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