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- PDB-28zt: Crystal structure of human DHX9 in complex with ATX-968 and ADP -

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Basic information

Entry
Database: PDB / ID: 28zt
TitleCrystal structure of human DHX9 in complex with ATX-968 and ADP
ComponentsATP-dependent RNA helicase A
KeywordsRNA BINDING PROTEIN / Helicase / RNA / Inhibitor / Cancer
Function / homology
Function and homology information


single-stranded 3'-5' DNA helicase activity / 3'-5' DNA/RNA helicase activity / regulatory region RNA binding / CRD-mediated mRNA stability complex / positive regulation of RNA export from nucleus / DNA-templated viral transcription / positive regulation of viral transcription / G-quadruplex unwinding activity / regulation of cytoplasmic translation / negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay ...single-stranded 3'-5' DNA helicase activity / 3'-5' DNA/RNA helicase activity / regulatory region RNA binding / CRD-mediated mRNA stability complex / positive regulation of RNA export from nucleus / DNA-templated viral transcription / positive regulation of viral transcription / G-quadruplex unwinding activity / regulation of cytoplasmic translation / negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay / RISC complex binding / CRD-mediated mRNA stabilization / triplex DNA binding / protein localization to cytoplasmic stress granule / nucleoside triphosphate diphosphatase activity / perichromatin fibrils / DEx/H-box helicases activate type I IFN and inflammatory cytokines production / alternative mRNA splicing, via spliceosome / positive regulation of interleukin-18 production / nuclear stress granule / 3'-5' RNA helicase activity / miRNA-mediated post-transcriptional gene silencing / regulation of defense response to virus by host / regulation of mRNA processing / RISC-loading complex / positive regulation of response to cytokine stimulus / RISC complex assembly / importin-alpha family protein binding / RIP-mediated NFkB activation via ZBP1 / siRNA binding / positive regulation of cytoplasmic translation / positive regulation of innate immune response / sequence-specific mRNA binding / RISC complex / RNA polymerase binding / cellular response to exogenous dsRNA / RNA polymerase II complex binding / positive regulation of interferon-alpha production / DNA replication origin binding / pyroptotic inflammatory response / 3'-5' DNA helicase activity / mRNA transport / mRNA Splicing - Major Pathway / positive regulation of interferon-beta production / positive regulation of fibroblast proliferation / positive regulation of DNA repair / positive regulation of DNA replication / DNA helicase activity / promoter-specific chromatin binding / DNA-templated transcription termination / chromatin DNA binding / positive regulation of interleukin-6 production / PKR-mediated signaling / RNA stem-loop binding / osteoblast differentiation / transcription coregulator activity / cytoplasmic ribonucleoprotein granule / mRNA Polyadenylation / positive regulation of inflammatory response / actin cytoskeleton / positive regulation of tumor necrosis factor production / ribonucleoside triphosphate phosphatase activity / rhythmic process / double-stranded RNA binding / single-stranded DNA binding / ribosome binding / protein-containing complex assembly / Dengue Virus-Host Interactions / double-stranded DNA binding / chromatin organization / RNA polymerase II-specific DNA-binding transcription factor binding / nuclear body / DNA replication / transcription coactivator activity / RNA helicase activity / single-stranded RNA binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / RNA helicase / ribonucleoprotein complex / innate immune response / mRNA binding / centrosome / regulation of transcription by RNA polymerase II / nucleolus / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / protein-containing complex / DNA binding / RNA binding / nucleoplasm / ATP binding / membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
DHX9, first double-stranded RNA binding domain / DHX9, second double-stranded RNA binding domain / DHX9, DEXH-box helicase domain / : / Helicase associated domain (HA2), ratchet-like / DEAD-box helicase, OB fold / Oligonucleotide/oligosaccharide-binding (OB)-fold / Helicase associated domain (HA2), winged-helix / Helicase-associated domain / Helicase associated domain (HA2) Add an annotation ...DHX9, first double-stranded RNA binding domain / DHX9, second double-stranded RNA binding domain / DHX9, DEXH-box helicase domain / : / Helicase associated domain (HA2), ratchet-like / DEAD-box helicase, OB fold / Oligonucleotide/oligosaccharide-binding (OB)-fold / Helicase associated domain (HA2), winged-helix / Helicase-associated domain / Helicase associated domain (HA2) Add an annotation / Double-stranded RNA binding motif / Double-stranded RNA binding motif / DNA/RNA helicase, ATP-dependent, DEAH-box type, conserved site / DEAH-box subfamily ATP-dependent helicases signature. / Double stranded RNA-binding domain (dsRBD) profile. / Double-stranded RNA-binding domain / DEAD/DEAH box helicase domain / DEAD/DEAH box helicase / Helicase conserved C-terminal domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / ADENOSINE-5'-DIPHOSPHATE / ATP-dependent RNA helicase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.4 Å
AuthorsKnopp, A. / Le Bihan, Y.-V. / van Montfort, R.L.M.
Funding support United Kingdom, Germany, 3items
OrganizationGrant numberCountry
Cancer Research UKC309/A8274 United Kingdom
Cancer Research UKC309/A11566 United Kingdom
Other private Germany
CitationJournal: J.Med.Chem. / Year: 2026
Title: Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8.
Authors: Read, B.J. / Ewens, C. / Gigante, F. / Thomas, J. / Felisberto-Rodrigues, C. / Alvarez Peres, S. / Tighe, C. / de Las Heras Ruiz, E. / Schiemann, K. / Malcolm, A.G. / McAndrew, P.C. / ...Authors: Read, B.J. / Ewens, C. / Gigante, F. / Thomas, J. / Felisberto-Rodrigues, C. / Alvarez Peres, S. / Tighe, C. / de Las Heras Ruiz, E. / Schiemann, K. / Malcolm, A.G. / McAndrew, P.C. / Stubbs, M. / Patani, H. / Costa, H.D.S. / Stoodley, K. / Pickard, L. / Busch, M. / Gunnell, E. / Silva, S. / Knopp, A. / Hallett, S.T. / Augustin, M. / Lammens, A. / Carter, M. / Meniconi, M. / Ballarotto, M. / Ainsley, J. / Meister, P. / Sethi, D. / Burke, R. / Scarpino, A. / Le Bihan, Y.V. / Gradler, U. / Blagg, J. / Workman, P. / Clarke, P.A. / Blum, A. / Esdar, C. / Bhalay, G. / van Montfort, R.L.M.
History
DepositionMar 3, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 2, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-dependent RNA helicase A
B: ATP-dependent RNA helicase A
C: ATP-dependent RNA helicase A
D: ATP-dependent RNA helicase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)460,43215
Polymers457,3614
Non-polymers3,07211
Water72140
1
A: ATP-dependent RNA helicase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,2144
Polymers114,3401
Non-polymers8733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: ATP-dependent RNA helicase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,2144
Polymers114,3401
Non-polymers8733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: ATP-dependent RNA helicase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,2144
Polymers114,3401
Non-polymers8733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: ATP-dependent RNA helicase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,7923
Polymers114,3401
Non-polymers4522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)119.611, 166.973, 293.495
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
ATP-dependent RNA helicase A / DEAH box protein 9 / DExH-box helicase 9 / Leukophysin / LKP / Nuclear DNA helicase II / NDH II / ...DEAH box protein 9 / DExH-box helicase 9 / Leukophysin / LKP / Nuclear DNA helicase II / NDH II / RNA helicase A


Mass: 114340.164 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHX9, DDX9, LKP, NDH2 / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q08211, RNA helicase
#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-A1BKX / (4M)-N-[3-chloro-5-(methanesulfonamido)phenyl]-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide


Mass: 421.921 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H16ClN3O3S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O
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: 3.2 Å3/Da / Density % sol: 61.61 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 150 nanoliters of DHX9 at 10 mg/mL with 5 mM ADP, 5 mM MgCl2 and 90 micromolar ATX-968, plus 150 nanoliters of a crystallisation solution consisting of 100 mM Morpheus buffer system 2 pH 7- ...Details: 150 nanoliters of DHX9 at 10 mg/mL with 5 mM ADP, 5 mM MgCl2 and 90 micromolar ATX-968, plus 150 nanoliters of a crystallisation solution consisting of 100 mM Morpheus buffer system 2 pH 7-8, 100 mM Morpheus carboxylic acids mix and 30-40% Morpheus precipitant mix 2, plus 40 nanoliters of seeds, against 70 microliters of crystallisation solution
PH range: 7 - 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 23, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3.4→49.73 Å / Num. obs: 81625 / % possible obs: 100 % / Redundancy: 13.6 % / Biso Wilson estimate: 117.5 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.151 / Rpim(I) all: 0.042 / Rrim(I) all: 0.157 / Net I/σ(I): 11.8 / Num. measured all: 1106095 / Scaling rejects: 1138
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.4-3.46143.6126167544120.50.9943.7471100
17.67-49.7311.40.02674316500.9940.0080.02769.795.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (26-JUL-2023)refinement
Aimless0.8.2data scaling
PHASERphasing
PDB_EXTRACT3.28data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.4→49.73 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.937 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.468
RfactorNum. reflection% reflectionSelection details
Rfree0.2583 4130 5.07 %RANDOM
Rwork0.2349 ---
obs0.2361 81523 100 %-
Displacement parametersBiso max: 287.88 Å2 / Biso mean: 151.28 Å2 / Biso min: 47.06 Å2
Baniso -1Baniso -2Baniso -3
1--10.7601 Å20 Å20 Å2
2--10.8467 Å20 Å2
3----0.0867 Å2
Refine analyzeLuzzati coordinate error obs: 0.51 Å
Refinement stepCycle: final / Resolution: 3.4→49.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms24496 0 192 40 24728
Biso mean--140.63 83.03 -
Num. residues----3365
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d8048SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4384HARMONIC5
X-RAY DIFFRACTIONt_it25230HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion3634SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact19450SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d25230HARMONIC20.007
X-RAY DIFFRACTIONt_angle_deg34522HARMONIC20.85
X-RAY DIFFRACTIONt_omega_torsion2.23
X-RAY DIFFRACTIONt_other_torsion17.24
LS refinement shellResolution: 3.4→3.42 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3609 75 4.6 %
Rwork0.3637 1556 -
all0.3635 1631 -
obs--99.82 %
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)
11.3608-0.43220.19910.7496-0.16731.89190.16160.04060.034-0.1047-0.0741-0.013-0.09090.0294-0.08750.0383-0.053-0.1706-0.34750.03540.011516.118944.50376.7788
21.91910.5096-0.45331.4865-0.21770.96040.03680.1284-0.0561-0.1420.0497-0.47750.00710.1824-0.0865-0.02190.103-0.058-0.2165-0.18220.12140.7111.660466.4289
31.4879-0.1942-0.52961.40410.08281.46940.0575-0.2650.01730.23620.02710.0606-0.32680.0281-0.0846-0.0109-0.02530.16410.10230.0305-0.351121.2153-23.4461-0.1661
41.52830.61880.08871.818-0.76854.29540.3323-0.25780.18420.5934-0.2219-0.243-1.08850.7225-0.11040.4759-0.3040.304-0.2794-0.2268-0.337843.610719.8097-14.4418
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|272 - A|1501 }A272 - 1501
2X-RAY DIFFRACTION2{ B|272 - B|1401 }B272 - 1401
3X-RAY DIFFRACTION3{ C|271 - C|1401 }C271 - 1401
4X-RAY DIFFRACTION4{ D|271 - D|1302 }D271 - 1302

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