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- EMDB-62807: ATR-ATRIP-bound with AMP-PNP -

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Basic information

Entry
Database: EMDB / ID: EMD-62807
TitleATR-ATRIP-bound with AMP-PNP
Map data
Sample
  • Cell: ATR-ATRIP
    • Protein or peptide: Serine/threonine-protein kinase ATR
    • Protein or peptide: ATR-interacting protein
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
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 / MutSalpha complex binding / establishment of protein-containing complex localization to telomere / histone H2AXS139 kinase activity / nuclear membrane disassembly / MutLalpha complex binding / 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 / MutSalpha complex binding / establishment of protein-containing complex localization to telomere / histone H2AXS139 kinase activity / nuclear membrane disassembly / MutLalpha complex binding / response to arsenic-containing substance / mitotic G2/M transition checkpoint / regulation of double-strand break repair / nucleobase-containing compound metabolic process / positive regulation of DNA damage response, signal transduction by p53 class mediator / 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 / Presynaptic phase of homologous DNA pairing and strand exchange / site of DNA damage / replicative senescence / Regulation of HSF1-mediated heat shock response / response to mechanical stimulus / interstrand cross-link repair / Activation of ATR in response to replication stress / 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 / cellular response to gamma radiation / PML body / G2/M DNA damage checkpoint / cellular response to UV / nuclear envelope / double-strand break repair / chromosome / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / DNA replication / 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 / : / Serine/threonine-protein kinase ATR, N-HEAT region / : / Serine/threonine-protein kinase ATR, M-HEAT region / UME domain / UME (NUC010) domain / Domain in UVSB PI-3 kinase, MEI-41 and ESR-1 / Serine/threonine-protein kinase ATR-like, HEAT repeats / HEAT repeat profile. ...ATR-interacting protein / : / Serine/threonine-protein kinase ATR, N-HEAT region / : / Serine/threonine-protein kinase ATR, M-HEAT region / UME domain / UME (NUC010) domain / Domain in UVSB PI-3 kinase, MEI-41 and ESR-1 / Serine/threonine-protein kinase ATR-like, HEAT repeats / 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: 6.29 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-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62807.png

Downloads & links

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Map

FileDownload / File: emd_62807.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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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: 0.23
Minimum - Maximum-0.3206389 - 0.8318625
Average (Standard dev.)0.0063481936 (±0.051198293)
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_62807_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62807_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: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

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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: 301.756781 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGEHGLELAS MIPALRELGS ATPEEYNTVV QKPRQILCQF IDRILTDVNV VAVELVKKTD SQPTSVMLLD FIQHIMKSSP LMFVNVSGS HEAKGSCIEF SNWIITRLLR IAATPSCHLL HKKICEVICS LLFLFKSKSP AIFGVLTKEL LQLFEDLVYL H RRNVMGHA ...String:
MGEHGLELAS MIPALRELGS ATPEEYNTVV QKPRQILCQF IDRILTDVNV VAVELVKKTD SQPTSVMLLD FIQHIMKSSP LMFVNVSGS HEAKGSCIEF SNWIITRLLR IAATPSCHLL HKKICEVICS LLFLFKSKSP AIFGVLTKEL LQLFEDLVYL H RRNVMGHA VEWPVVMSRF LSQLDEHMGY LQSAPLQLMS MQNLEFIEVT LLMVLTRIIA IVFFRRQELL LWQIGCVLLE YG SPKIKSL AISFLTELFQ LGGLPAQPAS TFFSSFLELL KHLVEMDTDQ LKLYEEPLSK LIKTLFPFEA EAYRNIEPVY LNM LLEKLC VMFEDGVLMR LKSDLLKAAL CHLLQYFLKF VPAGYESALQ VRKVYVRNIC KALLDVLGIE VDAEYLLGPL YAAL KMESM EIIEEIQCQT QQENLSSNSD GISPKRRRLS SSLNPSKRAP KQTEEIKHVD MNQKSILWSA LKQKAESLQI SLEYS GLKN PVIEMLEGIA VVLQLTALCT VHCSHQNMNC RTFKDCQHKS KKKPSVVITW MSLDFYTKVL KSCRSLLESV QKLDLE ATI DKVVKIYDAL IYMQVNSSFE DHILEDLCGM LSLPWIYSHS DDGCLKLTTF AANLLTLSCR ISDSYSPQAQ SRCVFLL TL FPRRIFLEWR TAVYNWALQS SHEVIRASCV SGFFILLQQQ NSCNRVPKIL IDKVKDDSDI VKKEFASILG QLVCTLHG M FYLTSSLTEP FSEHGHVDLF CRNLKATSQH ECSSSQLKAS VCKPFLFLLK KKIPSPVKLA FIDNLHHLCK HLDFREDET DVKAVLGTLL NLMEDPDKDV RVAFSGNIKH ILESLDSEDG FIKELFVLRM KEAYTHAQIS RNNELKDTLI LTTGDIGRAA KGDLVPFAL LHLLHCLLSK SASVSGAAYT EIRALVAAKS VKLQSFFSQY KKPICQFLVE SLHSSQMTAL PNTPCQNADV R KQDVAHQR EMALNTLSEI ANVFDFPDLN RFLTRTLQVL LPDLAAKASP AASALIRTLG KQLNVNRREI LINNFKYIFS HL VCSCSKD ELERALHYLK NETEIELGSL LRQDFQGLHN ELLLRIGEHY QQVFNGLSIL ASFASSDDPY QGPRDIISPE LMA DYLQPK LLGILAFFNM QLLSSSVGIE DKKMALNSLM SLMKLMGPKH VSSVRVKMMT TLRTGLRFKD DFPELCCRAW DCFV RCLDH ACLGSLLSHV IVALLPLIHI QPKETAAIFH YLIIENRDAV QDFLHEIYFL PDHPELKKIK AVLQEYRKET SESTD LQTT LQLSMKAIQH ENVDVRIHAL TSLKETLYKN QEKLIKYATD SETVEPIISQ LVTVLLKGCQ DANSQARLLC GECLGE LGA IDPGRLDFST TETQGKDFTF VTGVEDSSFA YGLLMELTRA YLAYADNSRA QDSAAYAIQE LLSIYDCREM ETNGPGH QL WRRFPEHVRE ILEPHLNTRY KSSQKSTDWS GVKKPIYLSK LGSNFAEWSA SWAGYLITKV RHDLASKIFT CCSIMMKH D FKVTIYLLPH ILVYVLLGCN QEDQQEVYAE IMAVLKHDDQ HTINTQDIAS DLCQLSTQTV FSMLDHLTQW ARHKFQALK AEKCPHSKSN RNKVDSMVST VDYEDYQSVT RFLDLIPQDT LAVASFRSKA YTRAVMHFES FITEKKQNIQ EHLGFLQKLY AAMHEPDGV AGVSAIRKAE PSLKEQILEH ESLGLLRDAT ACYDRAIQLE PDQIIHYHGV VKSMLGLGQL STVITQVNGV H ANRSEWTD ELNTYRVEAA WKLSQWDLVE NYLAADGKST TWSVRLGQLL LSAKKRDITA FYDSLKLVRA EQIVPLSAAS FE RGSYQRG YEYIVRLHML CELEHSIKPL FQHSPGDSSQ EDSLNWVARL EMTQNSYRAK EPILALRRAL LSLNKRPDYN EMV GECWLQ SARVARKAGH HQTAYNALLN AGESRLAELY VERAKWLWSK GDVHQALIVL QKGVELCFPE NETPPEGKNM LIHG RAMLL VGRFMEETAN FESNAIMKKY KDVTACLPEW EDGHFYLAKY YDKLMPMVTD NKMEKQGDLI RYIVLHFGRS LQYGN QFIY QSMPRMLTLW LDYGTKAYEW EKAGRSDRVQ MRNDLGKINK VITEHTNYLA PYQFLTAFSQ LISRICHSHD EVFVVL MEI IAKVFLAYPQ QAMWMMTAVS KSSYPMRVNR CKEILNKAIH MKKSLEKFVG DATRLTDKLL ELCNKPVDGS SSTLSMS TH FKMLKKLVEE ATFSEILIPL QSVMIPTLPS ILGTHANHAS HEPFPGHWAY IAGFDDMVEI LASLQKPKKI SLKGSDGK F YIMMCKPKDD LRKDCRLMEF NSLINKCLRK DAESRRRELH IRTYAVIPLN DECGIIEWVN NTAGLRPILT KLYKEKGVY MTGKELRQCM LPKSAALSEK LKVFREFLLP RHPPIFHEWF LRTFPDPTSW YSSRSAYCRS TAVMSMVGYI LGLGDRHGEN ILFDSLTGE CVHVDFNCLF NKGETFEVPE IVPFRLTHNM VNGMGPMGTE GLFRRACEVT MRLMRDQREP LMSVLKTFLH D PLVEWSKP VKGHSKAPLN ETGEVVNEKA KTHVLDIEQR LQGVIKTRNR VTGLPLSIEG HVHYLIQEAT DENLLCQMYL GW TPYM

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: 85.940664 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGTSAPGSK RRSEPPAPRP GPPPGTGHPP SKRARGFSAA AAPDPDDPFG AHGDFTADDL EELDTLASQA LSQCPAAARD VSSDHKVHR LLDGMSKNPS GKNRETVPIK DNFELEVLQA QYKELKEKMK VMEEEVLIKN GEIKILRDSL HQTESVLEEQ R RSHFLLEQ ...String:
MAGTSAPGSK RRSEPPAPRP GPPPGTGHPP SKRARGFSAA AAPDPDDPFG AHGDFTADDL EELDTLASQA LSQCPAAARD VSSDHKVHR LLDGMSKNPS GKNRETVPIK DNFELEVLQA QYKELKEKMK VMEEEVLIKN GEIKILRDSL HQTESVLEEQ R RSHFLLEQ EKTQALSDKE KEFSKKLQSL QSELQFKDAE MNELRTKLQT SERANKLAAP SVSHVSPRKN PSVVIKPEAC SP QFGKTSF PTKESFSANM SLPHPCQTES GYKPLVGRED SKPHSLRGDS IKQEEAQKSF VDSWRQRSNT QGSILINLLL KQP LIPGSS LSLCHLLSSS SESPAGTPLQ PPGFGSTLAG MSGLRTTGSY DGSFSLSALR EAQNLAFTGL NLVARNECSR DGDP AEGGR RAFPLCQLPG AVHFLPLVQF FIGLHCQALQ DLAAAKRSGA PGDSPTHSSC VSSGVETNPE DSVCILEGFS VTALS ILQH LVCHSGAVVS LLLSGVGADS AAGEGNRSLV HRLSDGDMTS ALRGVADDQG QHPLLKMLLH LLAFSSAATG HLQASV LTQ CLKVLVKLAE NTSCDFLPRF QCVFQVLPKC LSPETPLPSV LLAVELLSLL ADHDQLAPQL CSHSEGCLLL LLYMYIT SR PDRVALETQW LQLEQEVVWL LAKLGVQSPL PPVTGSNCQC NVEVVRALTV MLHRQWLTVR RAGGPPRTDQ QRRTVRCL R DTVLLLHGLS QKDKLFMMHC VEVLHQFDQV MPGVSMLIRG LPDVTDCEEA ALDDLCAAET DVEDPEVECG

UniProtKB: ATR-interacting protein

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Macromolecule #3: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / type: ligand / ID: 3 / Number of copies: 2 / Formula: AGS
Molecular weightTheoretical: 523.247 Da
Chemical component information

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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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 BIOQUANTUM (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: 6.29 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 6895
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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