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- PDB-7ale: Crystal structure of human PAICS in complex with inhibitor 69 -

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Basic information

Entry
Database: PDB / ID: 7ale
TitleCrystal structure of human PAICS in complex with inhibitor 69
ComponentsMultifunctional protein ADE2Multi-function printer
KeywordsLIGASE / De novo purine biosynthesis / nucleotide metabolism / cancer target / rational drug design
Function / homology
Function and homology information


phosphoribosylaminoimidazole carboxylase / 5-amino-4-imidazole carboxylate lyase activity / phosphoribosylaminoimidazole carboxylase activity / phosphoribosylaminoimidazolesuccinocarboxamide synthase / phosphoribosylaminoimidazolesuccinocarboxamide synthase activity / 'de novo' XMP biosynthetic process / purine nucleobase biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / GMP biosynthetic process ...phosphoribosylaminoimidazole carboxylase / 5-amino-4-imidazole carboxylate lyase activity / phosphoribosylaminoimidazole carboxylase activity / phosphoribosylaminoimidazolesuccinocarboxamide synthase / phosphoribosylaminoimidazolesuccinocarboxamide synthase activity / 'de novo' XMP biosynthetic process / purine nucleobase biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / GMP biosynthetic process / 'de novo' IMP biosynthetic process / cadherin binding / extracellular exosome / ATP binding / membrane / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Class II PurE / SAICAR synthetase signature 1. / SAICAR synthetase signature 2. / SAICAR synthetase, conserved site / SAICAR synthetase/ADE2, N-terminal / SAICAR synthetase / PurE domain / AIR carboxylase / AIR carboxylase
Similarity search - Domain/homology
Chem-OK8 / Chem-RLK / Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.95 Å
AuthorsSkerlova, J. / Marttila, P. / Unterlass, J. / Jemth, A.-S. / Henriksson, M. / Wakchaure, P. / Grube, M. / Warpman Berglund, U. / Homan, E. / Helleday, T. / Stenmark, P.
Funding support Sweden, European Union, 4items
OrganizationGrant numberCountry
Swedish Research Council2015-00162 Sweden
Swedish Research Council2018-03406 Sweden
European Research Council (ERC)TAROX-695376European Union
European Regional Development FundCZ.02.2.69/0.0/0.0/16_027/0008477European Union
CitationJournal: To Be Published
Title: Cellular and biochemical validation of a potent PAICS inhibitor
Authors: Marttila, P. / Skerlova, J. / Unterlass, J. / Jemth, A.-S. / Henriksson, M. / Wakchaure, P. / Grube, M. / Warpman Berglund, U. / Homan, E. / Stenmark, P. / Helleday, T.
History
DepositionOct 6, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Multifunctional protein ADE2
B: Multifunctional protein ADE2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,2106
Polymers94,2702
Non-polymers1,9394
Water0
1
A: Multifunctional protein ADE2
B: Multifunctional protein ADE2
hetero molecules

A: Multifunctional protein ADE2
B: Multifunctional protein ADE2
hetero molecules

A: Multifunctional protein ADE2
B: Multifunctional protein ADE2
hetero molecules

A: Multifunctional protein ADE2
B: Multifunctional protein ADE2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)384,83824
Polymers377,0818
Non-polymers7,75816
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_555x,-y,-z1
Buried area41990 Å2
ΔGint-226 kcal/mol
Surface area118540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.772, 152.440, 222.755
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Ens-ID: 1 / Beg auth comp-ID: LEU / Beg label comp-ID: LEU / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 0 / Auth seq-ID: 7 - 425 / Label seq-ID: 7 - 425

Dom-IDComponent-IDAuth asym-IDLabel asym-ID
11AA
22BB

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Components

#1: Protein Multifunctional protein ADE2 / Multi-function printer


Mass: 47135.102 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAICS, ADE2, AIRC, PAIS / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P22234, phosphoribosylaminoimidazolesuccinocarboxamide synthase, phosphoribosylaminoimidazole carboxylase
#2: Chemical ChemComp-RLK / 2-azanyl-~{N}-[2-bromanyl-5-[4-[3-(dimethylamino)propylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide


Mass: 515.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H27BrN6O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-OK8 / (2~{S})-2-[[5-azanyl-1-[(2~{R},3~{R},4~{S},5~{R})-3,4-bis(oxidanyl)-5-(phosphonooxymethyl)oxolan-2-yl]imidazol-4-yl]car bonylamino]butanedioic acid / SAICAR / Phosphoribosylaminoimidazolesuccinocarboxamide


Mass: 454.283 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H19N4O12P / Feature type: SUBJECT OF INVESTIGATION
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: 2.74 Å3/Da / Density % sol: 55.05 % / Description: small thin needle
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M MES/imidazole pH 6.5, 10% w/v PEG 8000, 20% v/v ethylene glycol, 0.02 M 1,6-hexanediol, 0.02 M 1-butanol, 0.02 M (RS)-1,2-propanediol, 0.02 M 2-propanol, 0.02 M 1,4-butanediol, and 0.02 M 1,3-propanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.95→49.541 Å / Num. obs: 22274 / % possible obs: 99.9 % / Redundancy: 12.828 % / Biso Wilson estimate: 51.347 Å2 / CC1/2: 0.985 / Rmerge(I) obs: 0.463 / Rrim(I) all: 0.483 / Χ2: 0.637 / Net I/σ(I): 7.01 / Num. measured all: 285722
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.95-3.1313.2411.9932.0546675353535250.7662.07499.7
3.13-3.3513.1381.4492.8743672332433240.8521.508100
3.35-3.6112.9330.9664.5340209310931090.911.006100
3.61-3.9512.8160.6326.5636795287128710.9460.659100
3.95-4.4212.8080.4028.8433557262026200.9780.419100
4.42-5.112.9280.29610.9230109232923290.9870.308100
5.1-6.2212.7480.3139.3625089196819680.9810.326100
6.22-8.7312.3310.19312.9619483158115800.9930.20199.9
8.73-49.54110.6890.10719.98101339609480.9960.11298.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
MOLREPphasing
REFMAC5.8.0232refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6yb9

6yb9


Resolution: 2.95→49.54 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.883 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.439 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2605 1113 5 %RANDOM
Rwork0.2249 ---
obs0.2267 21152 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 96.21 Å2 / Biso mean: 23.77 Å2 / Biso min: 3.58 Å2
Baniso -1Baniso -2Baniso -3
1--3.04 Å20 Å20 Å2
2--5.22 Å20 Å2
3----2.18 Å2
Refinement stepCycle: final / Resolution: 2.95→49.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6528 0 122 0 6650
Biso mean--32.31 --
Num. residues----838
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0136790
X-RAY DIFFRACTIONr_bond_other_d0.0350.0176376
X-RAY DIFFRACTIONr_angle_refined_deg1.5721.6589198
X-RAY DIFFRACTIONr_angle_other_deg2.3381.59214870
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5975836
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.73723.419310
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.63151208
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.3071532
X-RAY DIFFRACTIONr_chiral_restr0.0630.2882
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.027444
X-RAY DIFFRACTIONr_gen_planes_other0.0080.021326
Refine LS restraints NCS

Ens-ID: 1 / Number: 12611 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.12 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.952→3.028 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 80 -
Rwork0.306 1523 -
all-1603 -
obs--98.95 %

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