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- PDB-8boi: Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase wi... -

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Entry
Database: PDB / ID: 8boi
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 9
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / Inhibitor / Complex / Protein Tyrosine Kinase
Function / homology
Function and homology information


notochord cell development / notochord formation / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / lens fiber cell morphogenesis / axial mesoderm formation / cAMP metabolic process / regulation of blood vessel endothelial cell migration / pericyte cell differentiation / ephrin receptor activity ...notochord cell development / notochord formation / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / lens fiber cell morphogenesis / axial mesoderm formation / cAMP metabolic process / regulation of blood vessel endothelial cell migration / pericyte cell differentiation / ephrin receptor activity / leading edge membrane / negative regulation of chemokine production / response to growth factor / post-anal tail morphogenesis / activation of GTPase activity / bone remodeling / positive regulation of bicellular tight junction assembly / regulation of lamellipodium assembly / branching involved in mammary gland duct morphogenesis / EPH-Ephrin signaling / central nervous system neuron differentiation / RND1 GTPase cycle / RND2 GTPase cycle / tight junction / RND3 GTPase cycle / neural tube development / mammary gland epithelial cell proliferation / RHOV GTPase cycle / growth factor binding / EPHA-mediated growth cone collapse / regulation of cell adhesion mediated by integrin / RHOU GTPase cycle / lamellipodium membrane / RHOG GTPase cycle / EPH-ephrin mediated repulsion of cells / RAC2 GTPase cycle / RAC3 GTPase cycle / regulation of angiogenesis / ephrin receptor signaling pathway / regulation of ERK1 and ERK2 cascade / vasculogenesis / keratinocyte differentiation / RAC1 GTPase cycle / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / osteoclast differentiation / molecular function activator activity / negative regulation of angiogenesis / skeletal system development / protein localization to plasma membrane / cell chemotaxis / positive regulation of protein localization to plasma membrane / cell motility / receptor protein-tyrosine kinase / ruffle membrane / intrinsic apoptotic signaling pathway in response to DNA damage / osteoblast differentiation / cell migration / lamellipodium / virus receptor activity / angiogenesis / receptor complex / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / cadherin binding / inflammatory response / focal adhesion / cell surface / ATP binding / plasma membrane
Similarity search - Function
Ephrin type-A receptor 2, ligand binding domain / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / : / Ephrin receptor ligand binding domain / Ephrin type-A receptor 2 transmembrane domain / Receptor tyrosine kinase class V signature 1. / Receptor tyrosine kinase class V signature 2. ...Ephrin type-A receptor 2, ligand binding domain / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / : / Ephrin receptor ligand binding domain / Ephrin type-A receptor 2 transmembrane domain / Receptor tyrosine kinase class V signature 1. / Receptor tyrosine kinase class V signature 2. / Eph receptor ligand-binding domain profile. / Ephrin receptor ligand binding domain / Putative ephrin-receptor like / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Fibronectin type III domain / Growth factor receptor cysteine-rich domain superfamily / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Galactose-binding-like domain superfamily / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-R0O / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsLinhard, V. / Witt, K. / Gande, S. / Wollenhaupt, J. / Lennartz, F. / Weiss, M.S. / Schwalbe, H.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
CitationJournal: Chemistry / Year: 2023
Title: Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor.
Authors: Troster, A. / DiPrima, M. / Jores, N. / Kudlinzki, D. / Sreeramulu, S. / Gande, S.L. / Linhard, V. / Ludig, D. / Schug, A. / Saxena, K. / Reinecke, M. / Heinzlmeir, S. / Leisegang, M.S. / ...Authors: Troster, A. / DiPrima, M. / Jores, N. / Kudlinzki, D. / Sreeramulu, S. / Gande, S.L. / Linhard, V. / Ludig, D. / Schug, A. / Saxena, K. / Reinecke, M. / Heinzlmeir, S. / Leisegang, M.S. / Wollenhaupt, J. / Lennartz, F. / Weiss, M.S. / Kuster, B. / Tosato, G. / Schwalbe, H.
History
DepositionNov 15, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 22, 2023Group: Database references / Category: citation / Item: _citation.page_first / _citation.page_last
Revision 1.3Apr 5, 2023Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.4May 3, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.5Feb 7, 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

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Assembly

Deposited unit
A: Ephrin type-A receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0782
Polymers34,4631
Non-polymers6161
Water2,756153
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Also verified by NMR
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14050 Å2
Unit cell
Length a, b, c (Å)32.750, 107.450, 40.530
Angle α, β, γ (deg.)90.000, 108.610, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Ephrin type-A receptor 2 / Epithelial cell kinase / Tyrosine-protein kinase receptor ECK


Mass: 34462.840 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPHA2, ECK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29317, receptor protein-tyrosine kinase
#2: Chemical ChemComp-R0O / 4-methyl-~{N}-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide


Mass: 615.651 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H32F3N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 153 / 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: 1.96 Å3/Da / Density % sol: 37.28 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 37,5 % Precipitant Mix 4 (25% (v/v) Hexylene glycol, 25% (w/v) Poly(ethylene glycol) 1000, 25% (w/v) Poly(ethylene glycol) 3350), 0.1M Buffer system 3 pH 8.5 (1M BICINE, 1M Trizma base), 0. ...Details: 37,5 % Precipitant Mix 4 (25% (v/v) Hexylene glycol, 25% (w/v) Poly(ethylene glycol) 1000, 25% (w/v) Poly(ethylene glycol) 3350), 0.1M Buffer system 3 pH 8.5 (1M BICINE, 1M Trizma base), 0.15 M Carboxylic acids Mix (0.2M Ammonium acetate, 0.2M Potassium sodium tartrate tetrahydrate, 0.2M Sodium citrate tribasic dihydrate, 0.2M Sodium formate, 0.2M Sodium oxamate)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Dec 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.63→38.41 Å / Num. obs: 32353 / % possible obs: 97.6 % / Redundancy: 3.45 % / Biso Wilson estimate: 24.99 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.014 / Net I/σ(I): 7.8
Reflection shellResolution: 1.63→1.73 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 1.03 / Num. unique obs: 5132 / CC1/2: 0.4 / Rrim(I) all: 0.134 / % possible all: 95.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6q7d

6q7d


Resolution: 1.63→38.41 Å / SU ML: 0.2287 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.9444
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2111 1616 5 %
Rwork0.1791 30727 -
obs0.1807 32343 97.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.99 Å2
Refinement stepCycle: LAST / Resolution: 1.63→38.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2151 0 45 153 2349
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052378
X-RAY DIFFRACTIONf_angle_d0.83033231
X-RAY DIFFRACTIONf_chiral_restr0.0474343
X-RAY DIFFRACTIONf_plane_restr0.0125454
X-RAY DIFFRACTIONf_dihedral_angle_d12.4726938
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.63-1.680.33631320.30682509X-RAY DIFFRACTION94.97
1.68-1.730.31511320.28852511X-RAY DIFFRACTION96.53
1.73-1.790.29381330.25922512X-RAY DIFFRACTION96.92
1.79-1.860.3141330.23092546X-RAY DIFFRACTION97.14
1.87-1.950.24791350.21692558X-RAY DIFFRACTION97.89
1.95-2.050.25781350.19762565X-RAY DIFFRACTION97.58
2.05-2.180.18911350.17132569X-RAY DIFFRACTION98.33
2.18-2.350.20021350.16142565X-RAY DIFFRACTION98.18
2.35-2.590.21481350.16992565X-RAY DIFFRACTION98.43
2.59-2.960.19731380.16922610X-RAY DIFFRACTION99.1
2.96-3.730.21360.15392598X-RAY DIFFRACTION98.74
3.73-38.410.15991370.15082619X-RAY DIFFRACTION98.64
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)
15.088819481321.205891307130.928471731862.984385665820.1295605708673.97413153706-0.0176197035423-0.223562493005-0.0203104514784-0.1954229629930.1383875401-0.1846468568580.2223805088350.0882758969246-0.09337573635480.2637081674440.02872737919210.01333373646420.190976853714-0.08425868800570.290689294684-83.8849218556-28.991701865481.7751158666
20.9680198242810.3984252313190.02659718575442.7210800789-3.070111007785.01318837593-0.0475823797955-0.151656714729-0.0421862294738-0.03501367875380.1895152975320.2446561384360.119598312174-0.0510135028174-0.07562068880020.2429592095530.0208366777983-0.01061847823910.137378386391-0.002826800379080.275778842942-89.1502826233-27.580569844791.7626079025
30.7200812357790.2731382322350.0937776765271.22820897471-0.08419636126080.342495095257-0.03259306385490.0973459795889-0.13344183526-0.09422521154480.0227803620384-0.005263256224740.129989179580.03572214560140.01224251295160.203804068461-0.008088837308940.0102286042560.175882737486-0.01867289521220.154332463297-82.5495009816-16.001223123882.7879598536
41.23694306973-0.19578280582-0.2209547187230.9545272516270.1519092812861.19970206826-0.006269988170270.0386628064072-0.0748214456151-0.05602446014720.001310786277250.007226782521350.06681372515040.0112643972226-0.002126543706740.1194509689-0.007691406667140.005674011706530.1373806857360.01076318219020.122168427021-86.1683131001-6.4349473345186.8887445236
50.8026181361840.153656964213-0.09246717119580.6606706826510.868004088761.87245175281-0.0413371872062-0.124865492357-0.03506633917470.104876085436-0.0232576587388-0.06649024024570.1435126671320.01900922984350.01095886270340.172394874621-0.000481898232412-5.72570582544E-60.1915159366740.03837455222460.131344165683-83.9610327352-8.823846798103.83132104
61.53408730095-0.04085830544710.308550115851.08910231941-0.2812810520181.46147689535-0.0342156292614-0.08000057485280.04037795450460.0426905136903-0.0110725899305-0.0651363500968-0.0642228809220.03424371425210.04452458211240.126802527793-0.002707901830250.007674236371340.128398225698-0.0005774287323190.134343953569-80.8027480063.613757272895.9306397563
78.081029932750.3583990048670.7129898577981.85427907614-0.1622211181152.22627588186-0.0235309849217-0.4933433986550.0708438881934-0.0044233397201-0.0825351739011-0.510452384110.05205339481020.3865090862960.1174657115660.2745905172650.0196798391390.01077530238730.2669557100460.04528381618410.363834542054-64.282781629114.830920500491.2855455806
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 604 through 640 )604 - 6401 - 31
22chain 'A' and (resid 641 through 669 )641 - 66932 - 60
33chain 'A' and (resid 670 through 712 )670 - 71261 - 103
44chain 'A' and (resid 713 through 755 )713 - 755104 - 146
55chain 'A' and (resid 756 through 795 )756 - 795147 - 168
66chain 'A' and (resid 796 through 881 )796 - 881169 - 254
77chain 'A' and (resid 882 through 896 )882 - 896255 - 269

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