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- PDB-9o0r: Crystal structure of wild-type KRAS (GDP-bound) in complex with M... -

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Basic information

Entry
Database: PDB / ID: 9o0r
TitleCrystal structure of wild-type KRAS (GDP-bound) in complex with MRTX849 (adagrasib)
ComponentsGTPase KRas
KeywordsONCOPROTEIN/INHIBITOR / KRAS / RAS / K-ras / KRAS4b / inhibitor / MRTX849 / adagrasib / KRAZATI / oncoprotein / ONCOPROTEIN-INHIBITOR complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / 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 / Signaling by CSF3 (G-CSF) / 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 / positive regulation of glial cell proliferation / Tie2 Signaling / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / 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 / 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 / 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 / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / 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 / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
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 nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / ACETATE ION / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 Å
AuthorsChan, A.H. / Ashraf, M. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: J.Biol.Chem. / Year: 2025
Title: Biophysical and structural analysis of KRAS switch-II pocket inhibitors reveals allele-specific binding constraints.
Authors: Alexander, P. / Chan, A.H. / Rabara, D. / Swain, M. / Larsen, E.K. / Dyba, M. / Chertov, O. / Ashraf, M. / Champagne, A. / Lin, K. / Maciag, A. / Gillette, W.K. / Nissley, D.V. / McCormick, ...Authors: Alexander, P. / Chan, A.H. / Rabara, D. / Swain, M. / Larsen, E.K. / Dyba, M. / Chertov, O. / Ashraf, M. / Champagne, A. / Lin, K. / Maciag, A. / Gillette, W.K. / Nissley, D.V. / McCormick, F. / Simanshu, D.K. / Stephen, A.G.
History
DepositionApr 3, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release

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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)41,26314
Polymers38,6582
Non-polymers2,60512
Water2,108117
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6317
Polymers19,3291
Non-polymers1,3036
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6317
Polymers19,3291
Non-polymers1,3036
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.880, 42.598, 54.483
Angle α, β, γ (deg.)94.382, 98.610, 106.701
Int Tables number1
Space group name H-MP1
Space group name HallP1

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 19328.811 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

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Non-polymers , 5 types, 129 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A1B7W / Adagrasib / [(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile / Krazati


Mass: 604.117 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H35ClFN7O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.31 Å3/Da / Density % sol: 46.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 45 mM zinc acetate, 18% PEG 3350, 40 mM trans-4-hydroxy-L-proline

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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: Jul 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.8→53.44 Å / Num. obs: 28922 / % possible obs: 91 % / Redundancy: 3.3 % / CC1/2: 0.967 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.11 / Rrim(I) all: 0.201 / Net I/σ(I): 5.5
Reflection shellResolution: 1.8→1.84 Å / Redundancy: 3 % / Rmerge(I) obs: 0.556 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1433 / CC1/2: 0.817 / Rpim(I) all: 0.36 / Rrim(I) all: 0.665 / % possible all: 75.3

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.81→53.44 Å / SU ML: 0.2666 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 28.1903
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2475 2001 6.95 %
Rwork0.206 26787 -
obs0.2089 28788 90.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.77 Å2
Refinement stepCycle: LAST / Resolution: 1.81→53.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2643 0 156 117 2916
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00672847
X-RAY DIFFRACTIONf_angle_d1.16153865
X-RAY DIFFRACTIONf_chiral_restr0.0544422
X-RAY DIFFRACTIONf_plane_restr0.0079494
X-RAY DIFFRACTIONf_dihedral_angle_d18.51381075
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.81-1.850.35521240.3361649X-RAY DIFFRACTION76.92
1.85-1.90.34471380.28311758X-RAY DIFFRACTION85.21
1.9-1.960.32121250.25171811X-RAY DIFFRACTION84.58
1.96-2.020.26971440.22281964X-RAY DIFFRACTION93.32
2.02-2.090.28361530.21941969X-RAY DIFFRACTION94.27
2.09-2.180.28181610.21491987X-RAY DIFFRACTION93.96
2.18-2.270.25911490.22231972X-RAY DIFFRACTION94.02
2.27-2.390.26361370.20651971X-RAY DIFFRACTION92.99
2.39-2.540.26241430.21431958X-RAY DIFFRACTION93.21
2.54-2.740.24621370.22031827X-RAY DIFFRACTION86.56
2.74-3.020.271530.22262010X-RAY DIFFRACTION95.41
3.02-3.450.25051490.2022011X-RAY DIFFRACTION95.58
3.45-4.350.19871450.17591964X-RAY DIFFRACTION93.11
4.35-53.440.22951430.18741936X-RAY DIFFRACTION91.38
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)
10.328977306898-0.605597343379-0.1969128131970.8995122550240.6643222794670.270916466392-0.0484759217351-0.1647487457990.1993217989290.1447459094610.0822664049531-0.0531663668661-0.00453369784866-0.0776760382126-0.0007058058153390.1914742262450.0227385187881-0.02567292645030.1452228846720.01242506326090.18887721758914.25594691298.6622839486621.2113037115
20.136002699818-0.06752713931410.1997323107020.611703942421-0.01938095048740.209280285318-0.0581480967777-0.02610238750250.4366725331410.1045224259740.2792363780.406462180532-0.1917724036460.4240902104850.003189719180330.3589547471190.0565448396110.001869246119350.357285396043-0.04013291961240.4355677065473.2680399587313.934501855820.5783307393
30.5114621080330.171310278635-0.3203801977610.5491841723750.1809762525810.36402085941-0.200130166457-0.4480553601260.307787139840.6411371185220.437125431037-0.0544281922092-0.323763411924-0.2954597471160.000170982760520.4066289789050.0357148502233-0.05486956005740.370837236692-0.009505089547390.33217549937219.87331977979.8967024009426.1633676658
40.5725340583140.3378693584780.4162849049530.2167140718110.1769928819251.46285645446-0.191218399071-0.08275272426010.1616417722250.08523911508850.02397337809350.0429322147867-1.219296510310.133982396262-0.06798836537610.43758737677-0.0633476103714-0.03055866479780.2949763542040.03213186469240.250855265417.61770048314.51851125026.44879807167
50.3971592371530.489330698574-0.56794865890.942497678258-0.8240464476770.799003554680.0902090237658-0.0455977590536-0.07202807527060.03707203874580.01577604762050.03915260023850.2501070485220.168976360418-0.0002293789756520.2041819189870.004291769208530.0001114825876290.257915244412-0.0384345096990.24685751969112.77543776581.470028986958.30320818097
60.0777834894851-0.2294726875110.02714148173420.94737946497-0.1966741554980.08164696734610.2356885670620.2938884084050.1979738903120.08039755945070.0721456571598-0.100974251872-0.2036582002120.07771114748110.0007876169475950.30906778175-0.03840852323370.005037794704460.271259590024-0.054838796750.26734752516319.5575730039-0.93149281600611.9508588334
70.352834660652-0.295650447462-0.1200433087260.276704706310.07446361614740.114833243841-0.01313928258890.0329230358313-0.11670806820.1121315081720.1405371101671.146708631940.416186061479-0.5576791383320.03825937647440.159670490163-0.1022088165940.06845655773590.3663053959010.03746072084990.502917850157-1.13817241114-5.3852109902517.1354088559
80.446014492528-0.1753987953360.08141001446270.607227299467-0.6202293595411.0905404312-0.0129053229868-0.161834130063-0.3012569174080.3433998090090.0721322354520.09605014580640.8800458753180.1679500156640.01590038440960.297968946548-0.0140528844626-0.0009207338583930.266555721573-0.0195994981370.23260303134910.0421108152-6.3219132435317.5700127229
90.2126295259180.02845001546430.176343127890.131283376895-0.06547162611670.238346614204-0.0546118467582-0.206312871343-0.6113453071460.375647497973-0.02164576070220.007733973651360.1269681525680.02241049730157.09507341852E-50.2956418872070.0286181038676-0.03153177129930.3188960120810.003302107223040.32294699784720.5275622115-0.38830421990623.112833182
100.6237878835140.509269539066-0.1152446755290.6106253267220.4878522733040.1793749837030.1352184112680.23882133555-0.473200765289-0.1027892703030.1674200159750.08083716323920.3374343425060.1613291581630.05266105320270.2088009126980.01692589967630.02000696500350.27790247843-0.04717856515010.2161005197845.67139105709-19.017214317433.4822654507
110.1945901224050.203161763688-0.05635521550190.5072658614660.2514289305350.316483194620.03360981673660.299794646695-0.256656775092-0.158614241011-0.1032001998850.1924789988110.5007070597670.120239956614-0.0001917211237110.435826690942-0.0985414081560.02822937724140.372577253808-0.001118796453950.408137019689-5.12543951071-24.393530314434.1571261375
120.448665384755-0.1867459810040.4814274423210.534552655863-0.02762332976390.5380869268410.03289430485010.413897566694-0.246299103972-0.242417183519-0.103684119355-0.150647285167-0.00785025876442-0.325006948608-2.16003890503E-50.3828131913030.0642559691828-0.02956361698110.341249781462-0.02682933237210.24660912654511.40833443-20.232991446828.4805725418
130.4956489764320.2629745855970.1420234599960.3615120740870.003864890677240.07794674556070.4006182499150.330716794327-0.8187372004820.1929530783320.0232858772171-0.07593316046130.3590744633230.1797756558370.002229323491720.3900824315290.0724007442236-0.09089728864390.318187232096-0.001375013122040.3780693019588.56111288612-25.412350425948.6416652788
140.3232395757670.360513123480.01169872111981.150676507180.2359982520130.933504209406-0.070835793263-0.07419387982820.2005289462920.2693010571980.0852450768609-0.059302070466-0.05922410586890.00637831623835-0.0003898088170950.225375626380.02686403505460.006847078275610.237229270308-0.01218206302140.2269480303593.21305211974-10.470439747344.0462516402
151.273189653390.533803742449-0.6900176708440.656730564081-0.1350801804490.432850869791-0.008932289152910.1399009183520.408747593393-0.1421418739050.117190153260.342338026472-0.357962221941-0.0803208138283-3.17386933191E-50.254127980634-0.0125900006823-0.007350299550440.2449578018050.04387695457310.3262361127811.45638143074-4.0459201624837.3737060988
160.4082031546490.27792901813-0.5476123676010.220643214201-0.3522205765710.6950632784380.1097979516540.5674981215070.475159843829-0.3167699884490.0001923364352870.111018461722-0.3257513395220.0439094391180.0001468425074330.269773321167-0.005593352696930.0739323364350.2831083397270.006879701535230.31720681676411.9890390994-10.030333904231.5426699007
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 0 through 25 )AA0 - 251 - 26
22chain 'A' and (resid 26 through 37 )AA26 - 3727 - 38
33chain 'A' and (resid 38 through 57 )AA38 - 5739 - 58
44chain 'A' and (resid 58 through 74 )AA58 - 7459 - 75
55chain 'A' and (resid 75 through 104 )AA75 - 10476 - 105
66chain 'A' and (resid 105 through 116 )AA105 - 116106 - 117
77chain 'A' and (resid 117 through 126 )AA117 - 126118 - 127
88chain 'A' and (resid 127 through 151 )AA127 - 151128 - 152
99chain 'A' and (resid 152 through 166 )AA152 - 166153 - 167
1010chain 'B' and (resid 0 through 25 )BF0 - 251 - 26
1111chain 'B' and (resid 26 through 37 )BF26 - 3727 - 38
1212chain 'B' and (resid 38 through 57 )BF38 - 5739 - 58
1313chain 'B' and (resid 58 through 73 )BF58 - 7359 - 74
1414chain 'B' and (resid 74 through 126 )BF74 - 12675 - 127
1515chain 'B' and (resid 127 through 151 )BF127 - 151128 - 152
1616chain 'B' and (resid 152 through 166 )BF152 - 166153 - 167

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