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- PDB-6zli: CRYSTAL STRUCTURE OF KRAS-G12D IN COMPLEX WITH COMPOUND 13 AND GCP -

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Basic information

Entry
Database: PDB / ID: 6zli
TitleCRYSTAL STRUCTURE OF KRAS-G12D IN COMPLEX WITH COMPOUND 13 AND GCP
ComponentsGTPase KRas
KeywordsHYDROLASE / GTPase
Function / homology
Function and homology information


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 ...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 / p38MAPK events / FRS-mediated FGFR1 signaling / 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 / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / response to glucocorticoid / 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 / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / RAF activation / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / visual learning / 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 / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
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 / P-loop containing nucleotide triphosphate hydrolases ...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 / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / 2-[(2~{R})-piperidin-2-yl]-1~{H}-indole / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.73 Å
AuthorsKessler, D. / Fischer, G. / Boettcher, J.
CitationJournal: Future Med Chem / Year: 2020
Title: Drugging all RAS isoforms with one pocket.
Authors: Kessler, D. / Bergner, A. / Bottcher, J. / Fischer, G. / Dobel, S. / Hinkel, M. / Mullauer, B. / Weiss-Puxbaum, A. / McConnell, D.B.
History
DepositionJun 30, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: 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 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)40,0657
Polymers38,7742
Non-polymers1,2915
Water4,702261
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9323
Polymers19,3871
Non-polymers5462
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1334
Polymers19,3871
Non-polymers7463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.642, 73.164, 54.194
Angle α, β, γ (deg.)90, 103.15, 90
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: 19386.848 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: 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-QME / 2-[(2~{R})-piperidin-2-yl]-1~{H}-indole


Mass: 200.280 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C13H16N2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.16 Å3/Da / Density % sol: 43.01 %
Crystal growTemperature: 278 K / Method: vapor diffusion / Details: 51.8% MPD 50mM MES PH= 6.4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Aug 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.73→42.7915 Å / Num. obs: 23941 / % possible obs: 80.7 % / Redundancy: 3.1 % / Rmerge(I) obs: 0.051 / Rsym value: 0.051 / Net I/σ(I): 15.6
Reflection shellResolution: 1.747→1.862 Å / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1197 / CC1/2: 0.62

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
XDSMay 1, 2016data reduction
autoPROC1.1.7data scaling
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GJ8

6gj8


Resolution: 1.73→42.8 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.175 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.184 / SU Rfree Blow DPI: 0.154 / SU Rfree Cruickshank DPI: 0.152
RfactorNum. reflection% reflectionSelection details
Rfree0.2203 1203 -RANDOM
Rwork0.1785 ---
obs0.1805 23929 70.7 %-
Displacement parametersBiso mean: 17.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.1172 Å20 Å2-1.7336 Å2
2--0.2939 Å20 Å2
3----0.1767 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.73→42.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2672 0 81 261 3014
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082823HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.923830HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1026SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes480HARMONIC5
X-RAY DIFFRACTIONt_it2823HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion373SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2464SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.23
X-RAY DIFFRACTIONt_other_torsion17.23
LS refinement shellResolution: 1.73→1.81 Å /
RfactorNum. reflection
Rfree0.3013 30
Rwork0.2626 -
Refinement TLS params.

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)
11.05350.80560.3881.67030.32251.05510.03650.0603-0.00590.0603-0.0049-0.0692-0.0059-0.0692-0.0316-0.0398-0.001-0.0157-0.0154-0.0014-0.03713.6079-14.032938.6912
20.4767-0.2546-0.16441.67150.49051.4476-0.038-0.1219-0.0517-0.1219-0.0520.0272-0.05170.02720.0899-0.05360.0124-0.037-0.0183-0.0081-0.0215-2.6281-21.752512.9983
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 167
2X-RAY DIFFRACTION2{ B|* }B1 - 167

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