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- PDB-6bvk: Ras:SOS:Ras in complex with a small molecule activator -

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Basic information

Entry
Database: PDB / ID: 6bvk
TitleRas:SOS:Ras in complex with a small molecule activator
Components
  • (GTPase HRas) x 2
  • Son of sevenless homolog 1
KeywordsSIGNALING PROTEIN / Ras / SOS / inhibitor / ONCOPROTEIN / Protein-protein complex / MAPK
Function / homology
Function and homology information


midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / phospholipase C activator activity / regulation of T cell differentiation in thymus / GTPase complex / Interleukin-15 signaling ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / phospholipase C activator activity / regulation of T cell differentiation in thymus / GTPase complex / Interleukin-15 signaling / positive regulation of ruffle assembly / oncogene-induced cell senescence / positive regulation of small GTPase mediated signal transduction / Activation of RAC1 / Signaling by LTK / negative regulation of GTPase activity / blood vessel morphogenesis / positive regulation of miRNA metabolic process / epidermal growth factor receptor binding / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / T-helper 1 type immune response / leukocyte migration / positive regulation of wound healing / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / NRAGE signals death through JNK / defense response to protozoan / eyelid development in camera-type eye / Fc-epsilon receptor signaling pathway / roof of mouth development / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / B cell homeostasis / Activation of RAS in B cells / regulation of T cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / RET signaling / SOS-mediated signalling / positive regulation of protein targeting to membrane / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / hair follicle development / fibroblast growth factor receptor signaling pathway / Role of LAT2/NTAL/LAB on calcium mobilization / Signalling to RAS / Interleukin receptor SHC signaling / adipose tissue development / Signal attenuation / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EPHB-mediated forward signaling / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / myelination / positive regulation of GTPase activity / NCAM signaling for neurite out-growth / FCERI mediated Ca+2 mobilization / positive regulation of MAP kinase activity / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / intrinsic apoptotic signaling pathway / GTPase activator activity / insulin-like growth factor receptor signaling pathway / axon guidance / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Constitutive Signaling by Overexpressed ERBB2
Similarity search - Function
Son of sevenless (SoS) protein; Chain S, domain 1 / Son of sevenless (SoS) protein Chain: S domain 1 / Son of Sevenless (SoS) protein; Chain S, domain 2 / Ras guanine-nucleotide exchange factors catalytic domain / Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras-like guanine nucleotide exchange factor ...Son of sevenless (SoS) protein; Chain S, domain 1 / Son of sevenless (SoS) protein Chain: S domain 1 / Son of Sevenless (SoS) protein; Chain S, domain 2 / Ras guanine-nucleotide exchange factors catalytic domain / Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras guanine nucleotide exchange factor domain superfamily / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / RasGEF domain / Ras guanine-nucleotide exchange factors catalytic domain profile. / Guanine nucleotide exchange factor for Ras-like small GTPases / Ras guanine-nucleotide exchange factors catalytic domain / : / SOS1/NGEF-like PH domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Small GTPase, Ras-type / Small GTPase Ras domain profile. / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Histone-fold / Small GTP-binding protein domain / PH-like domain superfamily / P-loop containing nucleotide triphosphate hydrolases / Up-down Bundle / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EAV / FORMIC ACID / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase HRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.799 Å
AuthorsPhan, J. / Abbott, J. / Fesik, S.W.
Funding support United States, 1items
OrganizationGrant numberCountry
Lustgarden Foundation United States
Citation
Journal: J. Med. Chem. / Year: 2018
Title: Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.
Authors: Abbott, J.R. / Hodges, T.R. / Daniels, R.N. / Patel, P.A. / Kennedy, J.P. / Howes, J.E. / Akan, D.T. / Burns, M.C. / Sai, J. / Sobolik, T. / Beesetty, Y. / Lee, T. / Rossanese, O.W. / Phan, ...Authors: Abbott, J.R. / Hodges, T.R. / Daniels, R.N. / Patel, P.A. / Kennedy, J.P. / Howes, J.E. / Akan, D.T. / Burns, M.C. / Sai, J. / Sobolik, T. / Beesetty, Y. / Lee, T. / Rossanese, O.W. / Phan, J. / Waterson, A.G. / Fesik, S.W.
#1: Journal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2014
Title: Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.
Authors: Burns, M.C. / Sun, Q. / Daniels, R.N. / Camper, D. / Kennedy, J.P. / Phan, J. / Olejniczak, E.T. / Lee, T. / Waterson, A.G. / Rossanese, O.W. / Fesik, S.W.
History
DepositionDec 13, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2018Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase HRas
B: Son of sevenless homolog 1
C: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,87215
Polymers94,3783
Non-polymers1,49412
Water21,5821198
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8890 Å2
ΔGint-38 kcal/mol
Surface area35940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)184.421, 184.421, 179.008
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Components on special symmetry positions
IDModelComponents
11B-2862-

HOH

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein GTPase HRas / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


Mass: 18856.146 Da / Num. of mol.: 1 / Mutation: Y64A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01112
#2: Protein Son of sevenless homolog 1


Mass: 56589.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889
#3: Protein GTPase HRas / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


Mass: 18932.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01112

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Non-polymers , 7 types, 1210 molecules

#4: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-EAV / N-{1-[(5-chloro-1H-indol-3-yl)methyl]piperidin-4-yl}-6-methyl-L-tryptophanamide


Mass: 464.002 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30ClN5O
#7: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: CH2O2
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#9: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1198 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 4.03 Å3/Da / Density % sol: 69.49 %
Crystal growTemperature: 292 K / Method: vapor diffusion / Details: 0.1 M sodium acetate, 2.0 M sodium formate, pH 4.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.799→33.53 Å / Num. obs: 141274 / % possible obs: 99.93 % / Redundancy: 12 % / Rpim(I) all: 0.039 / Net I/σ(I): 18.5
Reflection shellResolution: 1.799→1.863 Å / Num. unique all: 6961 / Rpim(I) all: 0.392

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Processing

Software
NameVersionClassification
PHENIX(1.12rc1_2801: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.799→33.53 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.54
RfactorNum. reflection% reflection
Rfree0.1787 6876 4.87 %
Rwork0.1553 --
obs0.1564 141270 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.799→33.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6534 0 97 1203 7834
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077103
X-RAY DIFFRACTIONf_angle_d0.8439647
X-RAY DIFFRACTIONf_dihedral_angle_d14.6364384
X-RAY DIFFRACTIONf_chiral_restr0.0531045
X-RAY DIFFRACTIONf_plane_restr0.0051300
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7989-1.81930.26632220.22764356X-RAY DIFFRACTION99
1.8193-1.84070.24312100.22944450X-RAY DIFFRACTION100
1.8407-1.86310.25432360.21724455X-RAY DIFFRACTION100
1.8631-1.88670.23361950.20494443X-RAY DIFFRACTION100
1.8867-1.91160.20252200.19844429X-RAY DIFFRACTION100
1.9116-1.93770.20942640.19544419X-RAY DIFFRACTION100
1.9377-1.96540.22722610.19334412X-RAY DIFFRACTION100
1.9654-1.99480.19422490.17994420X-RAY DIFFRACTION100
1.9948-2.02590.18942080.16964483X-RAY DIFFRACTION100
2.0259-2.05910.18982290.16344439X-RAY DIFFRACTION100
2.0591-2.09460.18322140.15954451X-RAY DIFFRACTION100
2.0946-2.13270.17772550.1514446X-RAY DIFFRACTION100
2.1327-2.17370.18172510.15214409X-RAY DIFFRACTION100
2.1737-2.21810.19261930.15144509X-RAY DIFFRACTION100
2.2181-2.26630.16992040.15094479X-RAY DIFFRACTION100
2.2663-2.3190.17452350.15554462X-RAY DIFFRACTION100
2.319-2.3770.17452580.15484408X-RAY DIFFRACTION100
2.377-2.44120.17672450.15524472X-RAY DIFFRACTION100
2.4412-2.51310.18242060.15464499X-RAY DIFFRACTION100
2.5131-2.59410.18822350.14914486X-RAY DIFFRACTION100
2.5941-2.68680.18822230.15844454X-RAY DIFFRACTION100
2.6868-2.79430.18342510.16174477X-RAY DIFFRACTION100
2.7943-2.92150.18562980.15674421X-RAY DIFFRACTION100
2.9215-3.07540.18852530.1554482X-RAY DIFFRACTION100
3.0754-3.26790.15972530.14924479X-RAY DIFFRACTION100
3.2679-3.520.17482070.14244553X-RAY DIFFRACTION100
3.52-3.87380.13832240.13094538X-RAY DIFFRACTION100
3.8738-4.43320.14681910.12234600X-RAY DIFFRACTION100
4.4332-5.58120.14611790.13844660X-RAY DIFFRACTION100
5.5812-33.6420.18372070.16984803X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0230.02270.01650.03910.02630.05430.04280.008-0.0292-0.0168-0.00850.0880.073-0.038200.121-0.02180.01680.1316-0.01250.141819.647550.261862.348
20.02620.00660.04060.00750.00050.0386-0.0293-0.0917-0.01250.08880.0241-0.0266-0.0720.0828-0.00030.1194-0.05160.0180.1468-0.01990.113229.285345.112656.7654
30.01190.00490.0178-0.00520.00360.01320.0243-0.129-0.07990.1855-0.0640.05280.1648-0.0532-00.2038-0.04320.02260.17770.00690.126724.141946.06873.3244
40.05710.05570.01340.04870.02050.01390.1135-0.26840.13820.1245-0.03430.0391-0.04750.06440.00280.158-0.04630.0180.1771-0.03310.123827.294457.220474.7271
50.03410.0586-0.04260.0565-0.05070.03330.0442-0.03840.1759-0.0511-0.01480.0909-0.15840.048-00.158-0.0280.03130.1178-0.02130.186524.740866.13865.7562
60.0114-0.0105-0.01260.00610.00340.01270.0376-0.00290.04380.0292-0.0776-0.0487-0.04880.1079-00.1381-0.04160.01340.1678-0.01420.123634.683354.107160.7145
70.0856-0.1129-0.19350.18350.05170.3205-0.01950.00180.01270.0202-0.00420.03240.01460.041900.1114-0.02130.00160.12390.00390.092912.979431.117178.0127
80.0331-0.01780.01780.03590.05610.05490.10510.01280.070.05410.05540.0997-0.2807-0.0649-0.00010.1702-0.02380.0110.15170.01920.16459.554149.478852.5579
90.15160.0361-0.07750.3344-0.15320.5732-0.03280.019-0.0041-0.01440.0252-0.0147-0.00480.02890.0230.0458-0.02310.00920.0567-0.00680.053122.510233.801532.8561
10-0.0005-0.01020.0120.0477-0.03480.0134-0.04130.02230.12450.13110.0201-0.16690.03820.001200.12650.0209-0.00420.1245-0.00170.207131.74512.264941.6185
11-0.0029-0.0035-0.00040.007-0.00670.00160.02910.0344-0.06750.04710.04760.01060.10230.000300.30870.0462-0.12040.14770.07580.412532.237912.603755.8548
120.00060.0027-0.01190.00170.00180.003-0.0264-0.07340.0170.0494-0.1188-0.0451-0.10690.1106-00.20980.0522-0.09190.2330.0030.406439.978114.300646.027
130.01380.02180.05590.04950.04060.0878-0.0533-0.0221-0.0117-0.04070.001-0.1658-0.04850.0175-0.00080.0969-0.00080.00990.0830.00650.151629.467119.244736.0046
140.0027-0.007-0.03190.10860.01370.02670.06280.0488-0.0041-0.1209-0.02740.03430.01960.0312-00.12620.01880.01890.10780.00440.124823.44098.877431.5835
150.015-0.00350.01860.0116-0.01210.01970.0824-0.0385-0.0096-0.0539-0.02540.18730.10690.013-00.14790.00840.00890.1042-0.02570.179518.0925-1.869536.4868
160.004-0.00730.00770.0115-0.00550.00310.0097-0.0852-0.00940.0651-0.0063-0.0692-0.0243-0.034200.12830.02270.00510.1201-0.00690.128526.37071.063643.3012
170.0122-0.00610.00010.011-0.00300.03870.0160.035-0.0874-0.055-0.14870.1230.03740.0010.11110.03450.02670.1162-0.00360.186537.00593.365337.0193
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 36 )
2X-RAY DIFFRACTION2chain 'A' and (resid 37 through 52 )
3X-RAY DIFFRACTION3chain 'A' and (resid 53 through 76 )
4X-RAY DIFFRACTION4chain 'A' and (resid 77 through 116 )
5X-RAY DIFFRACTION5chain 'A' and (resid 117 through 151 )
6X-RAY DIFFRACTION6chain 'A' and (resid 152 through 166 )
7X-RAY DIFFRACTION7chain 'B' and (resid 565 through 723 )
8X-RAY DIFFRACTION8chain 'B' and (resid 724 through 768 )
9X-RAY DIFFRACTION9chain 'B' and (resid 769 through 1046 )
10X-RAY DIFFRACTION10chain 'C' and (resid 0 through 24 )
11X-RAY DIFFRACTION11chain 'C' and (resid 25 through 34 )
12X-RAY DIFFRACTION12chain 'C' and (resid 35 through 48 )
13X-RAY DIFFRACTION13chain 'C' and (resid 49 through 74 )
14X-RAY DIFFRACTION14chain 'C' and (resid 75 through 117 )
15X-RAY DIFFRACTION15chain 'C' and (resid 118 through 137 )
16X-RAY DIFFRACTION16chain 'C' and (resid 138 through 151 )
17X-RAY DIFFRACTION17chain 'C' and (resid 152 through 166 )

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Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

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