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- EMDB-62811: ATR-ATRIP bound with RP-3500 -

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Basic information

Entry
Database: EMDB / ID: EMD-62811
TitleATR-ATRIP bound with RP-3500
Map data
Sample
  • Cell: ATR-ATRIP
    • Protein or peptide: Serine/threonine-protein kinase ATR
    • Protein or peptide: ATR-interacting protein
  • Ligand: RP-3500
  • Ligand: ZINC ION
KeywordsATR-ATRIP inhibitor / CELL CYCLE
Function / homology
Function and homology information


ATR-ATRIP complex / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / establishment of protein-containing complex localization to telomere / MutSalpha complex binding / nuclear membrane disassembly / MutLalpha complex binding / regulation of double-strand break repair / response to arsenic-containing substance / mitotic G2/M transition checkpoint ...ATR-ATRIP complex / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / establishment of protein-containing complex localization to telomere / MutSalpha complex binding / nuclear membrane disassembly / MutLalpha complex binding / regulation of double-strand break repair / response to arsenic-containing substance / mitotic G2/M transition checkpoint / positive regulation of DNA damage response, signal transduction by p53 class mediator / nucleobase-containing compound metabolic process / protein localization to chromosome, telomeric region / HDR through Single Strand Annealing (SSA) / K63-linked polyubiquitin modification-dependent protein binding / Impaired BRCA2 binding to RAD51 / negative regulation of DNA replication / replication fork processing / site of DNA damage / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / Regulation of HSF1-mediated heat shock response / interstrand cross-link repair / Activation of ATR in response to replication stress / response to mechanical stimulus / regulation of cellular response to heat / positive regulation of telomere maintenance via telomerase / telomere maintenance / Meiotic synapsis / DNA damage checkpoint signaling / TP53 Regulates Transcription of DNA Repair Genes / Fanconi Anemia Pathway / G2/M DNA damage checkpoint / cellular response to gamma radiation / PML body / cellular response to UV / nuclear envelope / double-strand break repair / peptidyl-serine phosphorylation / chromosome / Processing of DNA double-strand break ends / protein autophosphorylation / Regulation of TP53 Activity through Phosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / DNA replication / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / response to xenobiotic stimulus / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA damage response / Golgi apparatus / DNA binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
ATR-interacting protein / UME domain / UME (NUC010) domain / Domain in UVSB PI-3 kinase, MEI-41 and ESR-1 / HEAT repeat profile. / HEAT, type 2 / : / FATC domain / PIK-related kinase, FAT / FAT domain ...ATR-interacting protein / UME domain / UME (NUC010) domain / Domain in UVSB PI-3 kinase, MEI-41 and ESR-1 / HEAT repeat profile. / HEAT, type 2 / : / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase ATR / ATR-interacting protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.79 Å
AuthorsWang G
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Sci Bull (Beijing) / Year: 2025
Title: Molecular architecture and inhibition mechanism of human ATR-ATRIP.
Authors: Guangxian Wang / Po Wang / Zexuan Zheng / Qingjun Zhang / Chenchen Xu / Xinyi Xu / Lingfei Jian / Zhanpeng Zhao / Gang Cai / Xuejuan Wang /
Abstract: The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans. Targeting ATR is the focus of oncology drug pipelines ...The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans. Targeting ATR is the focus of oncology drug pipelines with a number of potent, selective ATR inhibitors currently in clinical development. Here, we determined the cryo-EM structures of the human ATR-ATRIP complex in the presence of VE-822 and RP-3500, two ATR inhibitors currently in Phase II clinical trials, achieving an overall resolution of approximately 3 Å. These structures yield a near-complete atomic model of the ATR-ATRIP complex, revealing subunit stoichiometry, intramolecular and intermolecular interactions, and critical regulatory sites including an insertion in the PIKK regulatory domain (PRD). Structural comparison provides insights into the modes of action and selectivity of ATR inhibitors. The divergent binding modes near the solvent side and in the rear pocket area of VE-822 and RP-3500, particularly their disparate binding orientations, lead to varying conformational changes in the active site. Surprisingly, one ATR-ATRIP complex binds four VE-822 molecules, with two in the ATR active site and two at the ATR-ATR dimer interface. The binding and selectivity of RP-3500 depend on two bound water molecules, which may be further enhanced by the substitution of these bound waters. Our study provides a structural framework for understanding ATR regulation and holds promise for assisting future efforts in rational drug design targeting ATR.
History
DepositionDec 20, 2024-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62811.png

Downloads & links

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Map

FileDownload / File: emd_62811.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 384 pix.
= 314.88 Å		0.82 Å/pix.
x 384 pix.
= 314.88 Å		0.82 Å/pix.
x 384 pix.
= 314.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.64007574 - 1.2037814
Average (Standard dev.)0.0057570194 (±0.044412907)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 314.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62811_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_62811_half_map_2.map
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Sample components

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Entire : ATR-ATRIP

EntireName: ATR-ATRIP
Components
  • Cell: ATR-ATRIP
    • Protein or peptide: Serine/threonine-protein kinase ATR
    • Protein or peptide: ATR-interacting protein
  • Ligand: RP-3500
  • Ligand: ZINC ION

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Supramolecule #1: ATR-ATRIP

SupramoleculeName: ATR-ATRIP / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Serine/threonine-protein kinase ATR

MacromoleculeName: Serine/threonine-protein kinase ATR / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 301.001938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LASMIPALRE LGSATPEEYN TVVQKPRQIL CQFIDRILTD VNVVAVELVK KTDSQPTSVM LLDFIQHIMK SSPLMFVNVS GSHEAKGSC IEFSNWIITR LLRIAATPSC HLLHKKICEV ICSLLFLFKS KSPAIFGVLT KELLQLFEDL VYLHRRNVMG H AVEWPVVM ...String:
LASMIPALRE LGSATPEEYN TVVQKPRQIL CQFIDRILTD VNVVAVELVK KTDSQPTSVM LLDFIQHIMK SSPLMFVNVS GSHEAKGSC IEFSNWIITR LLRIAATPSC HLLHKKICEV ICSLLFLFKS KSPAIFGVLT KELLQLFEDL VYLHRRNVMG H AVEWPVVM SRFLSQLDEH MGYLQSAPLQ LMSMQNLEFI EVTLLMVLTR IIAIVFFRRQ ELLLWQIGCV LLEYGSPKIK SL AISFLTE LFQLGGLPAQ PASTFFSSFL ELLKHLVEMD TDQLKLYEEP LSKLIKTLFP FEAEAYRNIE PVYLNMLLEK LCV MFEDGV LMRLKSDLLK AALCHLLQYF LKFVPAGYES ALQVRKVYVR NICKALLDVL GIEVDAEYLL GPLYAALKME SMEI IEEIQ CQTQQENLSS NSDGISPKRR RLSSSLNPSK RAPKQTEEIK HVDMNQKSIL WSALKQKAES LQISLEYSGL KNPVI EMLE GIAVVLQLTA LCTVHCSHQN MNCRTFKDCQ HKSKKKPSVV ITWMSLDFYT KVLKSCRSLL ESVQKLDLEA TIDKVV KIY DALIYMQVNS SFEDHILEDL CGMLSLPWIY SHSDDGCLKL TTFAANLLTL SCRISDSYSP QAQSRCVFLL TLFPRRI FL EWRTAVYNWA LQSSHEVIRA SCVSGFFILL QQQNSCNRVP KILIDKVKDD SDIVKKEFAS ILGQLVCTLH GMFYLTSS L TEPFSEHGHV DLFCRNLKAT SQHECSSSQL KASVCKPFLF LLKKKIPSPV KLAFIDNLHH LCKHLDFRED ETDVKAVLG TLLNLMEDPD KDVRVAFSGN IKHILESLDS EDGFIKELFV LRMKEAYTHA QISRNNELKD TLILTTGDIG RAAKGDLVPF ALLHLLHCL LSKSASVSGA AYTEIRALVA AKSVKLQSFF SQYKKPICQF LVESLHSSQM TALPNTPCQN ADVRKQDVAH Q REMALNTL SEIANVFDFP DLNRFLTRTL QVLLPDLAAK ASPAASALIR TLGKQLNVNR REILINNFKY IFSHLVCSCS KD ELERALH YLKNETEIEL GSLLRQDFQG LHNELLLRIG EHYQQVFNGL SILASFASSD DPYQGPRDII SPELMADYLQ PKL LGILAF FNMQLLSSSV GIEDKKMALN SLMSLMKLMG PKHVSSVRVK MMTTLRTGLR FKDDFPELCC RAWDCFVRCL DHAC LGSLL SHVIVALLPL IHIQPKETAA IFHYLIIENR DAVQDFLHEI YFLPDHPELK KIKAVLQEYR KETSESTDLQ TTLQL SMKA IQHENVDVRI HALTSLKETL YKNQEKLIKY ATDSETVEPI ISQLVTVLLK GCQDANSQAR LLCGECLGEL GAIDPG RLD FSTTETQGKD FTFVTGVEDS SFAYGLLMEL TRAYLAYADN SRAQDSAAYA IQELLSIYDC REMETNGPGH QLWRRFP EH VREILEPHLN TRYKSSQKST DWSGVKKPIY LSKLGSNFAE WSASWAGYLI TKVRHDLASK IFTCCSIMMK HDFKVTIY L LPHILVYVLL GCNQEDQQEV YAEIMAVLKH DDQHTINTQD IASDLCQLST QTVFSMLDHL TQWARHKFQA LKAEKCPHS KSNRNKVDSM VSTVDYEDYQ SVTRFLDLIP QDTLAVASFR SKAYTRAVMH FESFITEKKQ NIQEHLGFLQ KLYAAMHEPD GVAGVSAIR KAEPSLKEQI LEHESLGLLR DATACYDRAI QLEPDQIIHY HGVVKSMLGL GQLSTVITQV NGVHANRSEW T DELNTYRV EAAWKLSQWD LVENYLAADG KSTTWSVRLG QLLLSAKKRD ITAFYDSLKL VRAEQIVPLS AASFERGSYQ RG YEYIVRL HMLCELEHSI KPLFQHSPGD SSQEDSLNWV ARLEMTQNSY RAKEPILALR RALLSLNKRP DYNEMVGECW LQS ARVARK AGHHQTAYNA LLNAGESRLA ELYVERAKWL WSKGDVHQAL IVLQKGVELC FPENETPPEG KNMLIHGRAM LLVG RFMEE TANFESNAIM KKYKDVTACL PEWEDGHFYL AKYYDKLMPM VTDNKMEKQG DLIRYIVLHF GRSLQYGNQF IYQSM PRML TLWLDYGTKA YEWEKAGRSD RVQMRNDLGK INKVITEHTN YLAPYQFLTA FSQLISRICH SHDEVFVVLM EIIAKV FLA YPQQAMWMMT AVSKSSYPMR VNRCKEILNK AIHMKKSLEK FVGDATRLTD KLLELCNKPV DGSSSTLSMS THFKMLK KL VEEATFSEIL IPLQSVMIPT LPSILGTHAN HASHEPFPGH WAYIAGFDDM VEILASLQKP KKISLKGSDG KFYIMMCK P KDDLRKDCRL MEFNSLINKC LRKDAESRRR ELHIRTYAVI PLNDECGIIE WVNNTAGLRP ILTKLYKEKG VYMTGKELR QCMLPKSAAL SEKLKVFREF LLPRHPPIFH EWFLRTFPDP TSWYSSRSAY CRSTAVMSMV GYILGLGDRH GENILFDSLT GECVHVDFN CLFNKGETFE VPEIVPFRLT HNMVNGMGPM GTEGLFRRAC EVTMRLMRDQ REPLMSVLKT FLHDPLVEWS K PVKGHSKA PLNETGEVVN EKAKTHVLDI EQRLQGVIKT RNRVTGLPLS IEGHVHYLIQ EATDENLLCQ MYLGWTPYM

UniProtKB: Serine/threonine-protein kinase ATR

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Macromolecule #2: ATR-interacting protein

MacromoleculeName: ATR-interacting protein / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.802465 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: WRQRSNTQGS ILINLLLKQP LIPGSSLSLC HLLSSSSESP AGTPLQPPGF GSTLAGMSGL RTTGSYDGSF SLSALREAQN LAFTGLNLV ARNECSRDGD PAEGGRRAFP LCQLPGAVHF LPLVQFFIGL HCQALQDLAA AKRSGAPGDS PTHSSCVSSG V ETNPEDSV ...String:
WRQRSNTQGS ILINLLLKQP LIPGSSLSLC HLLSSSSESP AGTPLQPPGF GSTLAGMSGL RTTGSYDGSF SLSALREAQN LAFTGLNLV ARNECSRDGD PAEGGRRAFP LCQLPGAVHF LPLVQFFIGL HCQALQDLAA AKRSGAPGDS PTHSSCVSSG V ETNPEDSV CILEGFSVTA LSILQHLVCH SGAVVSLLLS GVGADSAAGE GNRSLVHRLS DGDMTSALRG VADDQGQHPL LK MLLHLLA FSSAATGHLQ ASVLTQCLKV LVKLAENTSC DFLPRFQCVF QVLPKCLSPE TPLPSVLLAV ELLSLLADHD QLA PQLCSH SEGCLLLLLY MYITSRPDRV ALETQWLQLE QEVVWLLAKL GVQSPLPPVT GSNCQCNVEV VRALTVMLHR QWLT VRRAG GPPRTDQQRR TVRCLRDTVL LLHGLSQKDK LFMMHCVEVL HQFDQVMPGV SMLIRGLPDV TDCEEAALDD LCAAE TDVE DPEVECG

UniProtKB: ATR-interacting protein

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Macromolecule #3: RP-3500

MacromoleculeName: RP-3500 / type: ligand / ID: 3 / Number of copies: 2 / Formula: A1EIK
Molecular weightTheoretical: 410.47 Da

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.79 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 77631
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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