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- PDB-8dkb: Crystal Structure of human YEATS4 in complex with Pfizer small mo... -

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Basic information

Entry
Database: PDB / ID: 8dkb
TitleCrystal Structure of human YEATS4 in complex with Pfizer small molecule compound 3b
ComponentsYEATS domain-containing protein 4
KeywordsPROTEIN BINDING / histone binding / lysine-acetylated histone binding
Function / homology
Function and homology information


histone H3K18ac reader activity / histone H3K27ac reader activity / Activation of the TFAP2 (AP-2) family of transcription factors / regulation of double-strand break repair / NuA4 histone acetyltransferase complex / positive regulation of double-strand break repair via homologous recombination / structural constituent of cytoskeleton / nuclear matrix / nucleosome / mitotic cell cycle ...histone H3K18ac reader activity / histone H3K27ac reader activity / Activation of the TFAP2 (AP-2) family of transcription factors / regulation of double-strand break repair / NuA4 histone acetyltransferase complex / positive regulation of double-strand break repair via homologous recombination / structural constituent of cytoskeleton / nuclear matrix / nucleosome / mitotic cell cycle / HATs acetylate histones / nuclear membrane / regulation of apoptotic process / histone binding / regulation of cell cycle / chromatin remodeling / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / nucleoplasm / nucleus
Similarity search - Function
YEATS / : / YEATS superfamily / YEATS family / YEATS domain profile.
Similarity search - Domain/homology
Chem-SJI / YEATS domain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsDias, J.M. / Byrnes, L.J. / Varghese, A.H.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.
Authors: Londregan, A.T. / Aitmakhanova, K. / Bennett, J. / Byrnes, L.J. / Canterbury, D.P. / Cheng, X. / Christott, T. / Clemens, J. / Coffey, S.B. / Dias, J.M. / Dowling, M.S. / Farnie, G. / ...Authors: Londregan, A.T. / Aitmakhanova, K. / Bennett, J. / Byrnes, L.J. / Canterbury, D.P. / Cheng, X. / Christott, T. / Clemens, J. / Coffey, S.B. / Dias, J.M. / Dowling, M.S. / Farnie, G. / Fedorov, O. / Fennell, K.F. / Gamble, V. / Gileadi, C. / Giroud, C. / Harris, M.R. / Hollingshead, B.D. / Huber, K. / Korczynska, M. / Lapham, K. / Loria, P.M. / Narayanan, A. / Owen, D.R. / Raux, B. / Sahasrabudhe, P.V. / Ruggeri, R.B. / Saez, L.D. / Stock, I.A. / Thuma, B.A. / Tsai, A. / Varghese, A.E.
History
DepositionJul 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: 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: YEATS domain-containing protein 4
B: YEATS domain-containing protein 4
C: YEATS domain-containing protein 4
D: YEATS domain-containing protein 4
E: YEATS domain-containing protein 4
F: YEATS domain-containing protein 4
G: YEATS domain-containing protein 4
H: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,14816
Polymers145,8478
Non-polymers3,3018
Water6,017334
1
A: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: YEATS domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6432
Polymers18,2311
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.600, 109.300, 103.830
Angle α, β, γ (deg.)90.000, 95.680, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
YEATS domain-containing protein 4 / Glioma-amplified sequence 41 / Gas41 / NuMA-binding protein 1 / NuBI-1 / NuBI1


Mass: 18230.885 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YEATS4, GAS41 / Production host: Escherichia coli (E. coli) / References: UniProt: O95619
#2: Chemical
ChemComp-SJI / N-ethyl-1-{(3S,4S)-1-[(1-hydroxycyclohexyl)methyl]-3-methylpiperidin-4-yl}-2-methyl-1H-benzimidazole-5-carboxamide


Mass: 412.568 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C24H36N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 334 / 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: 2.35 Å3/Da / Density % sol: 47.57 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M sodium citrate tribasic dihydrate (pH 5.6), 2% (v/v) tacsimate (pH 5.0), and 16% PEG 3350, 0.1M Ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.58→103.32 Å / Num. obs: 26291 / % possible obs: 62 % / Redundancy: 3.4 % / CC1/2: 0.994 / Rsym value: 0.117 / Net I/σ(I): 8.7
Reflection shellResolution: 2.582→2.803 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1316 / CC1/2: 0.51 / Rsym value: 1.04 / % possible all: 14.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VNA

5vna


Resolution: 2.58→41.3 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.89 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.389
RfactorNum. reflection% reflectionSelection details
Rfree0.226 1286 4.89 %RANDOM
Rwork0.171 ---
obs0.174 26282 62 %-
Displacement parametersBiso max: 197.24 Å2 / Biso mean: 72.9 Å2 / Biso min: 15.6 Å2
Baniso -1Baniso -2Baniso -3
1-14.7564 Å20 Å2-9.3777 Å2
2---7.2453 Å20 Å2
3----7.5111 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 2.58→41.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8422 0 240 334 8996
Biso mean--73.6 44.2 -
Num. residues----1011
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3109SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1562HARMONIC5
X-RAY DIFFRACTIONt_it8935HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1123SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9818SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8935HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12138HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion17.84
LS refinement shellResolution: 2.58→2.73 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.339 20 3.8 %
Rwork0.2169 506 -
all0.221 526 -
obs--8.31 %
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)
10.69131.8601-1.76392.4468-2.97751.41660.16440.43010.30560.20440.32520.1438-0.6382-0.1652-0.48960.3825-0.0075-0.14150.0270.0839-0.0947-3.9834-3.069435.8681
21.20531.6727-1.11662.402-1.54650.085-0.28010.31230.0542-0.25790.17220.06720.5245-0.53890.10790.14140.0607-0.22580.02730.1278-0.11415.315621.18464.1752
33.6674-0.76960.09445.82770.7865.0710.230.1961-0.0565-0.3692-0.1983-0.38680.0781-0.0445-0.03160.0474-0.0277-0.0846-0.46350.0242-0.39187.254324.218164.1821
42.75090.53211.503810.9062.01618.2053-0.07640.0996-0.02930.9920.1331-0.82050.14820.1373-0.0567-0.1079-0.0164-0.3139-0.66020.0544-0.51869.3916-2.073358.9609
54.247-0.20790.19526.2362-2.04415.77070.1418-0.2961-0.4029-0.59350.03350.85020.634-0.712-0.1753-0.0336-0.1142-0.2179-0.4335-0.0401-0.3506-18.419127.074458.9062
66.6827-2.4564-0.33029.2691-0.07335.2005-0.18770.17150.43280.87560.2165-1.54970.06740.1747-0.0289-0.2426-0.0314-0.4624-0.6674-0.07-0.2444-20.719418.209913.5432
73.8656-0.50160.96937.65011.32687.2302-0.2111-0.09940.21110.0540.2405-0.4032-0.19570.2355-0.0295-0.02880.0932-0.2466-0.3692-0.0824-0.2361-17.1882-7.85539.4331
83.0825-0.69621.301212.67920.09284.1634-0.1183-0.32740.69121.61740.0825-0.7344-0.4858-0.32520.03580.13420.0223-0.3846-0.64220.038-0.53926.039645.453115.5826
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A19 - 144
2X-RAY DIFFRACTION2{ B|* }B20 - 145
3X-RAY DIFFRACTION3{ C|* }C20 - 148
4X-RAY DIFFRACTION4{ D|* }D20 - 144
5X-RAY DIFFRACTION5{ E|* }E19 - 145
6X-RAY DIFFRACTION6{ F|* }F19 - 144
7X-RAY DIFFRACTION7{ G|* }G19 - 144
8X-RAY DIFFRACTION8{ H|* }H21 - 146

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