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- PDB-6quw: Crystal Structure of KRAS-G12D in Complex with Natural Product-Li... -

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Basic information

Entry
Database: PDB / ID: 6quw
TitleCrystal Structure of KRAS-G12D in Complex with Natural Product-Like Compound 9b
ComponentsGTPase KRas
KeywordsONCOPROTEIN / PPI / KRAS / GTPase / cancer
Function / homology
Function and homology information


GMP binding / response to mineralocorticoid / 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 ...GMP binding / response to mineralocorticoid / 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 / 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 CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / 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 / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / 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 / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / RAF activation / liver development / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / cytokine-mediated signaling 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade
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 / Chem-JJQ / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.242 Å
AuthorsFischer, G. / Kessler, D. / Muellauer, B. / Wolkerstorfer, B.
CitationJournal: Chemistry / Year: 2019
Title: KRAS Binders Hidden in Nature.
Authors: Bergner, A. / Cockcroft, X. / Fischer, G. / Gollner, A. / Hela, W. / Kousek, R. / Mantoulidis, A. / Martin, L.J. / Mayer, M. / Mullauer, B. / Siszler, G. / Wolkerstorfer, B. / Kessler, D. / McConnell, D.B.
History
DepositionFeb 28, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 15, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / pdbx_unobs_or_zero_occ_atoms / software / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _software.name / _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

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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)40,0817
Polymers38,7742
Non-polymers1,3075
Water4,810267
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3260 Å2
ΔGint-30 kcal/mol
Surface area14490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.539, 72.097, 54.616
Angle α, β, γ (deg.)90.00, 103.31, 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: 19386.848 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Details: BIND CRYSTAL_ID 1016711 / Source: (natural) Homo sapiens (human)
Fragment: KRAS mutated (G12D). Nucleotide exchange to GPPCP. Cons..
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-JJQ / (3~{a}~{R},8~{b}~{S})-2,2,3~{a},8~{b}-tetramethyl-3,4-dihydro-1~{H}-pyrrolo[2,3-b]indole


Mass: 216.322 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 267 / 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: 2.1 Å3/Da / Density % sol: 41.48 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.4 / Details: 52% MPD, 0.06 M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Jul 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.242→53.1496 Å / Num. obs: 61942 / % possible obs: 68.6 % / Redundancy: 3.4 % / Biso Wilson estimate: 15.57 Å2 / Rmerge(I) obs: 0.032 / Rsym value: 0.032 / Net I/σ(I): 16.1
Reflection shellResolution: 1.242→1.342 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.751 / Mean I/σ(I) obs: 1.4 / Rsym value: 0.751 / % possible all: 16.6

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Processing

Software
NameVersionClassification
XDS(VERSION Jan 26data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
BUSTER2.11.7refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.242→35.9 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.954 / SU R Cruickshank DPI: 0.067 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.069 / SU Rfree Blow DPI: 0.067 / SU Rfree Cruickshank DPI: 0.066
RfactorNum. reflection% reflectionSelection details
Rfree0.21 3000 4.84 %RANDOM
Rwork0.193 ---
obs0.194 61943 68.3 %-
Displacement parametersBiso mean: 24.17 Å2
Baniso -1Baniso -2Baniso -3
1-0.2311 Å20 Å2-0.2422 Å2
2---0.0789 Å20 Å2
3----0.1523 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 1.242→35.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2659 0 82 267 3008
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112896HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.143966HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1057SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes495HARMONIC5
X-RAY DIFFRACTIONt_it2896HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.69
X-RAY DIFFRACTIONt_other_torsion16.05
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion380SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies8HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3595SEMIHARMONIC4
LS refinement shellResolution: 1.24→1.3 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2302 -4.92 %
Rwork0.2172 1178 -
all0.2178 1239 -
obs--9.59 %
Refinement TLS params.

L11: 0 °2 / L12: 0 °2 / L13: 0 °2 / L22: 0 °2 / L23: 0 °2 / L33: 0 °2 / S11: 0 Å ° / S12: 0 Å ° / S13: 0 Å ° / S21: 0 Å ° / S22: 0 Å ° / S23: 0 Å ° / S31: 0 Å ° / S32: 0 Å ° / S33: 0 Å ° / T11: 0 Å2 / T12: 0 Å2 / T13: 0 Å2 / T22: 0 Å2 / T23: 0 Å2 / T33: 0 Å2 / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDOrigin x (Å)Origin y (Å)Origin z (Å)
113.2411-14.459339.0438
2-2.8792-21.635513.2202
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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