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- PDB-8wwc: De novo design binder of HRAS -120-4 -

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Basic information

Entry
Database: PDB / ID: 8wwc
TitleDe novo design binder of HRAS -120-4
Components
  • De novo design protein 120-4
  • GTPase HRas
KeywordsDE NOVO PROTEIN / De novo design protein
Function / homology
Function and homology information


phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / positive regulation of ruffle assembly / negative regulation of GTPase activity / positive regulation of miRNA metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / T-helper 1 type immune response / positive regulation of wound healing / defense response to protozoan ...phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / positive regulation of ruffle assembly / negative regulation of GTPase activity / positive regulation of miRNA metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / T-helper 1 type immune response / positive regulation of wound healing / defense response to protozoan / 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 / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / positive regulation of protein targeting to membrane / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / adipose tissue development / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Schwann cell development / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / EPHB-mediated forward signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / intrinsic apoptotic signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / positive regulation of GTPase activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of epithelial cell proliferation / small monomeric GTPase / VEGFR2 mediated cell proliferation / regulation of actin cytoskeleton organization / animal organ morphogenesis / FCERI mediated MAPK activation / positive regulation of JNK cascade / Signaling by ERBB2 TMD/JMD mutants / RAF activation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cellular response to gamma radiation / G protein activity / Regulation of RAS by GAPs / positive regulation of type II interferon production / endocytosis / 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 / chemotaxis / cellular senescence / positive regulation of fibroblast proliferation / GDP binding / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / insulin receptor signaling pathway
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / 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
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase HRas
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWang, L. / Wang, S. / Liu, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: De novo design HRAS binder 120-4
Authors: Wang, L. / Wang, S. / Liu, Y.
History
DepositionOct 25, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: De novo design protein 120-4
A: GTPase HRas
B: GTPase HRas
D: De novo design protein 120-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9508
Polymers64,8574
Non-polymers1,0934
Water00
1
C: De novo design protein 120-4
A: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9754
Polymers32,4282
Non-polymers5472
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase HRas
D: De novo design protein 120-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9754
Polymers32,4282
Non-polymers5472
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.967, 89.967, 188.124
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Space group name HallP6c
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/2
#3: y,-x+y,z+1/2
#4: -y,x-y,z
#5: -x+y,-x,z
#6: -x,-y,z+1/2

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Components

#1: Protein De novo design protein 120-4


Mass: 13553.209 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#2: Protein GTPase HRas


Mass: 18875.191 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS / Production host: Escherichia coli 0.1197 (bacteria) / References: UniProt: P01112
#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
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: 3.48 Å3/Da / Density % sol: 64.67 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop
Details: 0.1M Bis Tris Propane pH7.5 0.2M Sodium nitrate 20% w/v PEG3350 10%v/v Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 14, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.8→48.85 Å / Num. obs: 21212 / % possible obs: 99.93 % / Redundancy: 20.5 % / Biso Wilson estimate: 62.36 Å2 / CC1/2: 0.982 / Net I/σ(I): 16.46
Reflection shellResolution: 2.8→2.9 Å / Num. unique obs: 2117 / CC1/2: 0.927

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→48.85 Å / SU ML: 0.3499 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.7435
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2467 2047 9.65 %
Rwork0.218 19156 -
obs0.2208 21203 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 87.26 Å2
Refinement stepCycle: LAST / Resolution: 2.8→48.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3994 0 66 0 4060
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034109
X-RAY DIFFRACTIONf_angle_d0.55675603
X-RAY DIFFRACTIONf_chiral_restr0.0436672
X-RAY DIFFRACTIONf_plane_restr0.0047725
X-RAY DIFFRACTIONf_dihedral_angle_d5.626600
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.860.32711470.32121261X-RAY DIFFRACTION100
2.87-2.940.40781120.27441295X-RAY DIFFRACTION100
2.94-3.020.32771350.26351273X-RAY DIFFRACTION99.93
3.02-3.10.29661300.24141291X-RAY DIFFRACTION100
3.11-3.210.28611410.25091263X-RAY DIFFRACTION100
3.21-3.320.33651490.2781263X-RAY DIFFRACTION100
3.32-3.450.26851270.23461282X-RAY DIFFRACTION99.93
3.45-3.610.26981590.21421242X-RAY DIFFRACTION100
3.61-3.80.27181210.19921285X-RAY DIFFRACTION100
3.8-4.040.20921420.19521267X-RAY DIFFRACTION100
4.04-4.350.21631490.19161280X-RAY DIFFRACTION99.93
4.35-4.780.20721610.1691247X-RAY DIFFRACTION99.93
4.79-5.480.2181480.20421261X-RAY DIFFRACTION100
5.48-6.90.30261060.25111336X-RAY DIFFRACTION100
6.91-48.850.19211200.21051310X-RAY DIFFRACTION99.58
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)
16.53576857795.22915209872-3.11339474325.02668027321-1.467291333695.71125768498-0.2437921909930.43421959579-0.00907876409373-0.2043166203250.149771304295-0.2066189963710.0553655873358-0.1869979142980.06136596030360.2384382012020.0340125363994-0.04986630675990.2749422927480.001308986152870.5346615416149.56846298902-9.798655171764.31059681518
24.77996092164-1.12751385805-4.02911102921.99951044033-3.952143458135.73027734050.2435700354160.01450583178590.366408714369-0.781885354934-0.177453394647-0.04785348204710.07063857484550.52703420722-0.08767150679120.331799675333-0.0350187054722-0.02916417603390.43592633324-0.1370472633320.78350271145124.5054449349-15.95499743795.51143517407
39.82551018311-0.8847583730272.693481545188.73636184655-1.490405710961.58501387474-0.0155870408833-3.38536135331.109721973391.66069097232-0.80117498703-0.695121409052-0.744556879981.969280292341.041309548281.57261574449-0.387133616392-0.2192027544532.524155293460.4437232566230.48726277388221.8574848711-18.10108186938.513964174
48.443771764150.631228091661-5.027073701354.00517257990.7324307288753.24411361623-0.158619001283-1.89888378999-1.25506502931.34106545371-1.12285084414-0.6358397076610.6945811352441.54375438771.058553240941.269003818770.3527722313060.03233143533611.465264859810.3832917822040.68012021998516.8616305316-20.175607477933.7500756488
58.348393614450.566635627526-0.5642760171618.13120196819-0.1505700972673.0511852845-1.08015048318-0.535989859311-1.36896015634-0.874037155351-0.614315930139-0.1007808503592.320063502770.5520985973121.271175152281.31793784698-0.03458755349730.1064142452861.042385568860.1546176480180.55096876892510.3116677122-25.825609102633.8939542459
66.727901962013.170572935543.719515275172.628319203990.3937691193513.691353418490.980561394809-2.69166160705-0.6293111342910.20583852646-1.676471434860.07420528153741.566123428670.03952552441620.1305506802211.750875301620.3980178802040.1544550470252.296872510950.6399296975780.8700027955817.5932172816-26.8335269741.8094057396
72.505147621043.441453538572.186512557994.787833403742.999253445161.93499098849-0.863091150108-0.3163148909920.966394454259-1.03372889350.7990092231050.474438463241-0.318749937073-0.56851638726-0.05517499807980.895675069153-0.0832640398397-0.3121328619391.484292025480.3643694455861.0774696590720.5037139458-12.4378667284-36.9878343076
81.79827895348-1.694597419360.5607504297382.744994603880.4024690184750.927108371323-0.623714541677-1.786279638720.827386846367-0.06181011127650.2459016072571.17346289956-0.287239617314-1.349271485420.4240572457360.5288196356010.753362693591-0.309478987392.571517701220.5914689757541.894387970873.02980626715-16.5779363715-34.3742894885
91.882125684592.543040723831.730278734777.313652494180.4836426437142.40825116018-0.4056444708290.6555125022980.480677433362-1.452262463710.314550824177-0.5856564465842.136603434760.6398543572930.01280594113141.188752295260.294429810511-0.08315088157041.280095753820.2674305120660.57683695499119.6783131385-21.7590241316-37.728034305
105.310651744120.8637609052290.7112178229377.97079142854-3.389470784967.99959185331-0.84162047951.20139461329-0.525497267886-1.631067608280.689000485952-0.1700299878420.845017186370.4958162786510.1413699927161.12478962233-0.181030857018-0.08480444731211.185900542330.05163889652020.79980622278123.6086226945-25.568369645-35.7223235578
116.771368765640.3655595757882.167409625414.18409483627-3.453364841963.86170983838-0.6207984835050.643419731781-0.784559406232-0.230666314076-0.0492799685365-0.133922445611.29474197388-1.16030317520.584708149421.13426721031-0.29518268674-0.1097265759090.968948894862-0.03646038988080.61970675402116.4688426144-29.8948753209-33.2864712764
124.109661848330.7986834896721.649683781199.01075355957-2.804637854342.320558543420.2637414306171.74020711099-0.274131117816-2.32837137046-0.3222078284610.804991943106-0.364894411405-0.9908499558690.09786392142491.199703507560.121628127745-0.3679415275641.52106956296-0.156655606090.75870403236413.5418063969-21.1209004685-40.7430696208
136.88599716642-2.309131590061.006180838417.16654441083-3.209649168673.45617726111-0.08196034581380.5081324536620.57404445327-0.806184968343-1.362453475340.4562621352173.14181073079-0.107415626841.027445669731.79250146845-0.306283357401-0.2942436158571.23529231268-0.3581839444680.64033368816413.766270392-28.4165940817-45.389169629
148.28161339314-2.23654762578-3.011310880574.511654445881.879115203925.690562641730.211001296751.313740802070.0925362193351-0.606924390587-0.0206501740340.3434946747440.0210965326907-0.729390587471-0.1877902332070.397081490676-0.0545860678742-0.138530825550.5394912411920.1205026994090.42844476177319.4365259447-19.6232745926-17.9029501687
157.21120091641-2.961821812790.3448455267193.03510596899-3.305940827046.09770448236-0.07143066345440.8339631666261.10565334822-0.05244627125730.184194622396-0.451331870355-0.691912305252-0.112243813999-0.1097202935310.407592951749-0.01503334581710.002169853577210.3728346106010.08226965108160.51999547682831.692026195-12.3460930399-14.6368726638
165.127512844680.0861129914028-0.8715801098896.351947330860.7784711795815.1455122569-0.112114413473-0.1920299763630.4513406492210.334025871060.162542813880.39984008443-0.0550965264798-0.0165505827557-0.05166818108360.2760046566610.00284938528742-0.02320903928190.2433110718320.09610644402560.39456205561827.5189894992-19.4187039498-5.03128474301
174.04464115482-2.862278355090.747967057446.418611241160.9050737016554.95034821354-0.195311766104-1.22980235881-0.841600958640.9370273798470.1344023423010.1728554843540.792895467783-0.1404553825870.0827380622760.4712159353990.097474324202-0.00768828611110.5122503509630.1921270608020.54177153928815.2847345461-19.175576885917.2382292133
185.76825041943-2.74094943665-2.073246787031.419298440611.97092500378.89004164464-1.02251960038-1.258953534610.05466592247621.756239687980.892198974662-0.09219588396920.4881788163280.3033030700230.01039701785420.9079964796160.229187607314-0.1242287597670.5680785565690.1243405653180.50951590765624.0132591048-23.169176159816.8062350314
195.987898766480.04891487670921.297774993434.852063598550.8861336010526.69925941743-0.289363781495-1.49695683290.3375450308910.9971598289910.398815030674-0.446613488121-0.1357166584680.444382405526-0.1190073857570.4831479565750.00544551267138-0.115733777470.570660599150.07874389191680.49251706032521.6310623768-11.861870395618.120727396
202.71876377111-0.8954485410441.520279596046.619162131932.208531162696.10670254072-0.2622347993550.01658260886561.472496162130.6326285798990.430409092731-0.355085229238-0.5463242004110.86090428723-0.07282447461920.387571374608-0.0117329309869-0.07112039643590.436992417348-0.06809573898350.50660009358617.2684599629-2.8458179239212.7832040369
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'B' and (resid 117 through 151 )BD117 - 151117 - 151
22chain 'B' and (resid 152 through 166 )BD152 - 166152 - 166
33chain 'D' and (resid 9 through 45 )DF9 - 451 - 36
44chain 'D' and (resid 46 through 68 )DF46 - 6837 - 59
55chain 'D' and (resid 69 through 86 )DF69 - 8660 - 77
66chain 'D' and (resid 87 through 118 )DF87 - 11878 - 108
77chain 'C' and (resid 6 through 26 )CA6 - 261 - 21
88chain 'C' and (resid 27 through 31 )CA27 - 3122 - 26
99chain 'C' and (resid 32 through 58 )CA32 - 5827 - 53
1010chain 'C' and (resid 59 through 68 )CA59 - 6854 - 63
1111chain 'C' and (resid 69 through 87 )CA69 - 8764 - 82
1212chain 'C' and (resid 88 through 105 )CA88 - 10583 - 100
1313chain 'C' and (resid 106 through 118 )CA106 - 118101 - 113
1414chain 'A' and (resid 1 through 67 )AB1 - 671 - 67
1515chain 'A' and (resid 68 through 116 )AB68 - 11668 - 116
1616chain 'A' and (resid 117 through 166 )AB117 - 166117 - 166
1717chain 'B' and (resid 1 through 36 )BD1 - 361 - 36
1818chain 'B' and (resid 37 through 46 )BD37 - 4637 - 46
1919chain 'B' and (resid 47 through 83 )BD47 - 8347 - 83
2020chain 'B' and (resid 84 through 116 )BD84 - 11684 - 116

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