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- PDB-6gj5: CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH 15 -

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Basic information

Entry
Database: PDB / ID: 6gj5
TitleCRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH 15
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / KRAS 4B / K-RAS 2 / KI-RAS / C-K-RAS / C-KI-RAS / GTPASE KRAS
Function / homology
Function and homology information


forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / 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 / 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:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / GDP binding / 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 / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / Ras protein signal transduction / negative regulation of neuron apoptotic process / mitochondrial outer membrane / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family 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 / P-loop containing nucleotide triphosphate hydrolases ...Small GTPase, Ras-type / small GTPase Ras family 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 / P-loop containing nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-F0N / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.499 Å
AuthorsKessler, D. / Mcconnell, D.M. / Mantoulidis, A.
Funding support United States, Austria, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P50A095103 United States
Austrian Science Fund854341 Austria
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: Drugging an undruggable pocket on KRAS.
Authors: Kessler, D. / Gmachl, M. / Mantoulidis, A. / Martin, L.J. / Zoephel, A. / Mayer, M. / Gollner, A. / Covini, D. / Fischer, S. / Gerstberger, T. / Gmaschitz, T. / Goodwin, C. / Greb, P. / ...Authors: Kessler, D. / Gmachl, M. / Mantoulidis, A. / Martin, L.J. / Zoephel, A. / Mayer, M. / Gollner, A. / Covini, D. / Fischer, S. / Gerstberger, T. / Gmaschitz, T. / Goodwin, C. / Greb, P. / Haring, D. / Hela, W. / Hoffmann, J. / Karolyi-Oezguer, J. / Knesl, P. / Kornigg, S. / Koegl, M. / Kousek, R. / Lamarre, L. / Moser, F. / Munico-Martinez, S. / Peinsipp, C. / Phan, J. / Rinnenthal, J. / Sai, J. / Salamon, C. / Scherbantin, Y. / Schipany, K. / Schnitzer, R. / Schrenk, A. / Sharps, B. / Siszler, G. / Sun, Q. / Waterson, A. / Wolkerstorfer, B. / Zeeb, M. / Pearson, M. / Fesik, S.W. / McConnell, D.B.
History
DepositionMay 16, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 14, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 30, 2022Group: Author supporting evidence / Database references / Derived calculations
Category: database_2 / pdbx_audit_support ...database_2 / pdbx_audit_support / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _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
Revision 1.4Jan 17, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4678
Polymers38,7422
Non-polymers1,7266
Water6,449358
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2344
Polymers19,3711
Non-polymers8633
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2344
Polymers19,3711
Non-polymers8633
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.074, 40.043, 94.284
Angle α, β, γ (deg.)90.00, 101.14, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 19370.781 Da / Num. of mol.: 2 / Mutation: C118S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116
#2: Chemical ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-F0N / (3~{S})-3-[2-[(2~{R})-pyrrolidin-2-yl]-1~{H}-indol-3-yl]-2,3-dihydroisoindol-1-one


Mass: 317.384 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H19N3O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 358 / 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: 2.01 Å3/Da / Density % sol: 38.85 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 30% PEG3350, 0.2 M potassium acetate

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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 24, 2015
RadiationMonochromator: Monochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.499→36.748 Å / Num. obs: 49619 / % possible obs: 99.64 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 2.7
Reflection shellResolution: 1.499→1.553 Å

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Processing

Software
NameVersionClassification
PHENIX(1.13rc1_2961: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EPV

4epv


Resolution: 1.499→36.748 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.05
RfactorNum. reflection% reflection
Rfree0.2028 2393 4.82 %
Rwork0.1843 --
obs0.1852 49610 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.499→36.748 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2590 0 114 358 3062
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042820
X-RAY DIFFRACTIONf_angle_d1.123836
X-RAY DIFFRACTIONf_dihedral_angle_d19.2191068
X-RAY DIFFRACTIONf_chiral_restr0.074422
X-RAY DIFFRACTIONf_plane_restr0.004487
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4993-1.52990.29081200.25422761X-RAY DIFFRACTION99
1.5299-1.56310.25831390.22842750X-RAY DIFFRACTION100
1.5631-1.59950.24841450.22862763X-RAY DIFFRACTION100
1.5995-1.63950.2621540.22342705X-RAY DIFFRACTION100
1.6395-1.68380.25491510.21552781X-RAY DIFFRACTION100
1.6838-1.73340.24491370.20962767X-RAY DIFFRACTION100
1.7334-1.78930.22121290.20512768X-RAY DIFFRACTION100
1.7893-1.85330.26841380.21142795X-RAY DIFFRACTION100
1.8533-1.92750.21831210.19912813X-RAY DIFFRACTION100
1.9275-2.01520.21941230.19622806X-RAY DIFFRACTION100
2.0152-2.12140.20621290.1932779X-RAY DIFFRACTION100
2.1214-2.25430.24541560.18922766X-RAY DIFFRACTION100
2.2543-2.42840.18931520.18532772X-RAY DIFFRACTION100
2.4284-2.67270.20211700.19272789X-RAY DIFFRACTION100
2.6727-3.05920.19661560.18482787X-RAY DIFFRACTION100
3.0592-3.85370.18391350.16172818X-RAY DIFFRACTION100
3.8537-36.75910.16621380.1642797X-RAY DIFFRACTION96
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)
14.71831.0148-0.19842.3961-0.25722.6347-0.20620.0744-0.6270.05870.0806-0.04080.2519-0.23970.12420.2209-0.00950.03770.1086-0.01090.1791-15.6428-20.1485-8.4746
24.10691.3095-1.05783.0213-0.5392.0361-0.2067-0.0643-0.50940.06680.0192-0.2180.24680.07140.18960.29650.00410.04890.12430.00490.221-15.9041-23.1811-6.0535
37.5544-1.3024-1.71685.13570.98485.3631-1.00021.0798-0.5372-1.10930.6067-0.29530.1420.08180.00980.4816-0.15810.09410.3568-0.07970.2476-16.0591-21.7985-22.8266
43.41681.80920.31592.8403-0.45952.4859-0.4290.94670.2073-0.55460.3069-0.0273-0.0031-0.10760.09190.2688-0.04670.00180.2840.04580.135-12.058-10.2744-18.6948
52.78250.1594-0.6573.60790.93443.1358-0.19760.12510.8382-0.24370.1136-0.1467-0.3309-0.16960.11810.2122-0.02260.00380.08420.07540.1776-11.3635-7.4895-11.4993
64.32161.5864-1.00282.18560.12041.1746-0.09140.14970.54530.02620.10850.0995-0.1576-0.0584-0.02530.22530.0262-0.00480.1070.02850.1767-17.0141-7.5786-7.1057
73.9856-0.1078-0.48551.7564-0.66891.9592-0.08370.53750.1019-0.14790.0039-0.1544-0.01530.40370.01160.1039-0.0176-0.00060.29690.03120.16042.29657.9912-39.9202
82.4859-1.0113-0.05963.1503-0.03730.077-0.13091.68350.1773-0.94120.1132-0.1983-0.12040.1385-0.05640.3124-0.1478-0.07590.7466-0.03580.1918-5.90416.2417-49.8978
96.30044.42633.37835.27426.19388.7819-0.16750.61510.4939-0.03390.0880.1079-0.18450.3735-0.03910.2191-0.04190.00090.39640.08440.27957.825911.4386-41.8319
104.65010.6648-0.89242.2336-0.05323.1434-0.1283-0.0513-0.33960.11420.0131-0.32740.14550.48680.03440.11650.0152-0.02070.22590.03790.16163.23254.1855-35.6319
114.1242-2.91532.98043.2195-0.72374.73780.0279-0.6473-1.13270.2204-0.154-0.14141.1339-0.1023-0.07210.32330.01180.01340.24190.1080.3369-5.6218-5.076-30.303
123.14021.1569-1.66573.09790.35192.8670.0046-0.2124-0.20490.3118-0.06870.15960.177-0.0502-0.0140.1465-0.02510.03080.16890.03940.1615-7.4084.4011-30.9113
133.37150.9537-1.3983.0444-0.55272.12210.1439-0.20280.26530.3376-0.05990.0969-0.16610.2076-0.0580.1512-0.02410.00340.18220.03020.1616-2.814110.4893-28.3361
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 25 )
2X-RAY DIFFRACTION2chain 'A' and (resid 26 through 58 )
3X-RAY DIFFRACTION3chain 'A' and (resid 59 through 74 )
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 104 )
5X-RAY DIFFRACTION5chain 'A' and (resid 105 through 126 )
6X-RAY DIFFRACTION6chain 'A' and (resid 127 through 167 )
7X-RAY DIFFRACTION7chain 'B' and (resid 0 through 25 )
8X-RAY DIFFRACTION8chain 'B' and (resid 26 through 36 )
9X-RAY DIFFRACTION9chain 'B' and (resid 37 through 46 )
10X-RAY DIFFRACTION10chain 'B' and (resid 47 through 86 )
11X-RAY DIFFRACTION11chain 'B' and (resid 87 through 103 )
12X-RAY DIFFRACTION12chain 'B' and (resid 104 through 126 )
13X-RAY DIFFRACTION13chain 'B' and (resid 127 through 169 )

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