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- PDB-6ob3: Crystal structure of G13D-KRAS (GMPPNP-bound) in complex with GAP... -

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Basic information

Entry
Database: PDB / ID: 6ob3
TitleCrystal structure of G13D-KRAS (GMPPNP-bound) in complex with GAP-related domain (GRD) of neurofibromin (NF1)
Components
  • GTPase KRas
  • Neurofibromin
KeywordsSIGNALING PROTEIN/GTP Binding / KRAS / RAS / KRAS4b / NF1 / GAP / Neurofibromin / G13D / SIGNALING PROTEIN-GTP Binding complex
Function / homology
Function and homology information


regulation of glial cell differentiation / forebrain astrocyte development / regulation of cell-matrix adhesion / negative regulation of neuroblast proliferation / metanephros development / negative regulation of oligodendrocyte differentiation / regulation of intracellular signal transduction / smooth muscle tissue development / regulation of blood vessel endothelial cell migration / camera-type eye morphogenesis ...regulation of glial cell differentiation / forebrain astrocyte development / regulation of cell-matrix adhesion / negative regulation of neuroblast proliferation / metanephros development / negative regulation of oligodendrocyte differentiation / regulation of intracellular signal transduction / smooth muscle tissue development / regulation of blood vessel endothelial cell migration / camera-type eye morphogenesis / forebrain morphogenesis / sympathetic nervous system development / cell communication / peripheral nervous system development / myelination in peripheral nervous system / phosphatidylcholine binding / collagen fibril organization / artery morphogenesis / phosphatidylethanolamine binding / pigmentation / adrenal gland development / regulation of bone resorption / regulation of postsynapse organization / spinal cord development / response to mineralocorticoid / GMP binding / negative regulation of endothelial cell proliferation / LRR domain binding / response to isolation stress / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / regulation of angiogenesis / RAS signaling downstream of NF1 loss-of-function variants / positive regulation of GTPase activity / RUNX3 regulates p14-ARF / negative regulation of fibroblast proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Schwann cell development / Signalling to RAS / extracellular matrix organization / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / positive regulation of Ras protein signal transduction / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / negative regulation of MAPK cascade / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / visual learning / 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 / liver development / GRB2 events in ERBB2 signaling / Downstream signal transduction / response to glucocorticoid / negative regulation of cell migration / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / wound healing / phosphatidylinositol 3-kinase/protein kinase B signal transduction / VEGFR2 mediated cell proliferation / GTPase activator activity / small monomeric GTPase / brain development / FCERI mediated MAPK activation / female pregnancy
Similarity search - Function
: / PH domain-like / Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins (rasGAP) domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins (rasGAP) domain profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain ...: / PH domain-like / Ras GTPase-activating protein / Ras GTPase-activating protein, conserved site / Ras GTPase-activating proteins (rasGAP) domain signature. / GTPase-activator protein for Ras-like GTPase / Ras GTPase-activating proteins (rasGAP) domain profile. / GTPase-activator protein for Ras-like GTPases / Ras GTPase-activating domain / Divergent CRAL/TRIO domain / CRAL-TRIO lipid binding domain profile. / Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) / CRAL-TRIO lipid binding domain / CRAL-TRIO lipid binding domain superfamily / Rho GTPase activation protein / 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 / PH-like domain superfamily / Armadillo-type fold / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas / Neurofibromin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsTran, T.H. / Dharmaiah, S. / Simanshu, D.K.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis.
Authors: Rabara, D. / Tran, T.H. / Dharmaiah, S. / Stephens, R.M. / McCormick, F. / Simanshu, D.K. / Holderfield, M.
History
DepositionMar 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Nov 13, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: Neurofibromin
C: GTPase KRas
D: Neurofibromin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,43316
Polymers97,2574
Non-polymers2,17612
Water5,639313
1
A: GTPase KRas
B: Neurofibromin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,8329
Polymers48,6292
Non-polymers1,2037
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: GTPase KRas
D: Neurofibromin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6017
Polymers48,6292
Non-polymers9725
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.677, 97.169, 155.525
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11(chain A and (resid 1 through 30 or (resid 31...
21(chain C and (resid 1 through 93 or resid 95 through 117 or resid 119 through 166))
12(chain B and (resid 1219 through 1268 or (resid 1269...
22(chain D and (resid 1219 through 1285 or resid 1287...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111METMETASPASP(chain A and (resid 1 through 30 or (resid 31...AA1 - 302 - 31
121GLUGLUGLUGLU(chain A and (resid 1 through 30 or (resid 31...AA3132
131GLYGLYLYSLYS(chain A and (resid 1 through 30 or (resid 31...AA0 - 1691 - 170
141GLYGLYLYSLYS(chain A and (resid 1 through 30 or (resid 31...AA0 - 1691 - 170
151GLYGLYLYSLYS(chain A and (resid 1 through 30 or (resid 31...AA0 - 1691 - 170
161GLYGLYLYSLYS(chain A and (resid 1 through 30 or (resid 31...AA0 - 1691 - 170
211METMETILEILE(chain C and (resid 1 through 93 or resid 95 through 117 or resid 119 through 166))CC1 - 932 - 94
221HISHISLYSLYS(chain C and (resid 1 through 93 or resid 95 through 117 or resid 119 through 166))CC95 - 11796 - 118
231ASPASPHISHIS(chain C and (resid 1 through 93 or resid 95 through 117 or resid 119 through 166))CC119 - 166120 - 167
112GLYGLYALAALA(chain B and (resid 1219 through 1268 or (resid 1269...BB1219 - 126812 - 61
122ASPASPASPASP(chain B and (resid 1219 through 1268 or (resid 1269...BB126962
132GLYGLYSERSER(chain B and (resid 1219 through 1268 or (resid 1269...BB1219 - 146312 - 256
142GLYGLYSERSER(chain B and (resid 1219 through 1268 or (resid 1269...BB1219 - 146312 - 256
152GLYGLYSERSER(chain B and (resid 1219 through 1268 or (resid 1269...BB1219 - 146312 - 256
162GLYGLYSERSER(chain B and (resid 1219 through 1268 or (resid 1269...BB1219 - 146312 - 256
212GLYGLYMETMET(chain D and (resid 1219 through 1285 or resid 1287...DD1219 - 128512 - 78
222PHEPHESERSER(chain D and (resid 1219 through 1285 or resid 1287...DD1287 - 131280 - 105
232ASPASPVALVAL(chain D and (resid 1219 through 1285 or resid 1287...DD1313 - 1317106 - 110
242ASPASPSERSER(chain D and (resid 1219 through 1285 or resid 1287...DD1217 - 146310 - 256
252ASPASPSERSER(chain D and (resid 1219 through 1285 or resid 1287...DD1217 - 146310 - 256
262ASPASPSERSER(chain D and (resid 1219 through 1285 or resid 1287...DD1217 - 146310 - 256
272ASPASPSERSER(chain D and (resid 1219 through 1285 or resid 1287...DD1217 - 146310 - 256

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ACBD

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


Mass: 19386.848 Da / Num. of mol.: 2 / Mutation: G13D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P01116
#2: Protein Neurofibromin / Neurofibromatosis-related protein NF-1


Mass: 29241.848 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NF1 / Production host: unidentified baculovirus / References: UniProt: P21359

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Non-polymers , 5 types, 325 molecules

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


Mass: 522.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#6: Chemical
ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / Source method: isolated from a natural source / Formula: H2O

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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: 3.23 Å3/Da / Density % sol: 61.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES pH 6.0 and 25% Pentaerythritol propoxylate (5/4 PO/OH)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.1→97.169 Å / Num. obs: 72838 / % possible obs: 99.6 % / Redundancy: 4.811 % / Biso Wilson estimate: 49.658 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.052 / Rrim(I) all: 0.059 / Χ2: 1.158 / Net I/σ(I): 17.26 / Num. measured all: 350416
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.1-2.234.8850.6792.68115520.8910.76298.9
2.23-2.384.6010.3994.19109590.9510.45199.7
2.38-2.575.0940.2696.42102550.9780.3100
2.57-2.814.9660.1649.7394430.990.18399.9
2.81-3.154.8670.09115.8885910.9960.10299.9
3.15-3.634.5570.04727.0875560.9980.05399.4
3.63-4.454.8780.03142.4864860.9990.03499.9
4.45-6.284.6460.02647.5650690.9990.02999.5
6.28-97.1694.4390.01956.23292710.02199.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6OB2

6ob2


Resolution: 2.1→77.763 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.18
Details: Based on various parameters, the authors decided to cut-off the resolution to 2.10 Ang, and that value was used for calculating data collection statistics and for the structure refinement
RfactorNum. reflection% reflection
Rfree0.2259 1779 2.45 %
Rwork0.186 --
obs0.1869 72678 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 133.75 Å2 / Biso mean: 57.5982 Å2 / Biso min: 29.86 Å2
Refinement stepCycle: final / Resolution: 2.1→77.763 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6576 0 129 313 7018
Biso mean--69.45 60.23 -
Num. residues----828
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1499X-RAY DIFFRACTION12.411TORSIONAL
12C1499X-RAY DIFFRACTION12.411TORSIONAL
21B2149X-RAY DIFFRACTION12.411TORSIONAL
22D2149X-RAY DIFFRACTION12.411TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.15680.39261360.322554145550100
2.1568-2.22030.33691330.296653565489100
2.2203-2.29190.341350.275338547399
2.2919-2.37390.32091350.247753865521100
2.3739-2.46890.27751360.227954305566100
2.4689-2.58130.26731370.213754025539100
2.5813-2.71740.28511360.211154505586100
2.7174-2.88760.27981370.214854455582100
2.8876-3.11060.2541370.214454445581100
3.1106-3.42360.21331360.19315438557499
3.4236-3.9190.2241380.17155145652100
3.919-4.93740.17671390.139655415680100
4.9374-77.81580.17221440.15555741588599
Refinement TLS params.Method: refined / Origin x: 16.8414 Å / Origin y: -12.7081 Å / Origin z: -19.4087 Å
111213212223313233
T0.2786 Å20.0204 Å2-0.0032 Å2-0.5463 Å20.0102 Å2--0.2802 Å2
L0.3915 °20.295 °2-0.1613 °2-0.7205 °2-0.2577 °2--0.3438 °2
S-0.0306 Å °0.1179 Å °0.0002 Å °-0.0472 Å °-0.0163 Å °-0.1056 Å °-0.0219 Å °0.0125 Å °0.0529 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA0 - 169
2X-RAY DIFFRACTION1allB1219 - 1463
3X-RAY DIFFRACTION1allC1 - 166
4X-RAY DIFFRACTION1allD1217 - 1463
5X-RAY DIFFRACTION1allW1 - 328
6X-RAY DIFFRACTION1allL1 - 12

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