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- PDB-8s4f: Human carbonic anhydrase I covalently bound to AV21-08 -

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Basic information

Entry
Database: PDB / ID: 8s4f
TitleHuman carbonic anhydrase I covalently bound to AV21-08
ComponentsCarbonic anhydrase 1
KeywordsLYASE / DRUG DESIGN / CARBONIC ANHYDRASE / BENZENESULFONAMIDE / METAL-BINDING / LYASE-LYASE INHIBITOR COMPLEX
Function / homology
Function and homology information


hydro-lyase activity / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / cyanamide hydratase / cyanamide hydratase activity / arylesterase activity / Reversible hydration of carbon dioxide / carbonic anhydrase / carbonate dehydratase activity / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen ...hydro-lyase activity / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / cyanamide hydratase / cyanamide hydratase activity / arylesterase activity / Reversible hydration of carbon dioxide / carbonic anhydrase / carbonate dehydratase activity / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen / extracellular exosome / zinc ion binding / cytosol / cytoplasm
Similarity search - Function
Carbonic anhydrase, alpha-class, conserved site / Alpha-carbonic anhydrases signature. / Carbonic anhydrase, alpha-class / Alpha carbonic anhydrase domain / Alpha carbonic anhydrase domain superfamily / Eukaryotic-type carbonic anhydrase / Alpha-carbonic anhydrases profile. / Eukaryotic-type carbonic anhydrase
Similarity search - Domain/homology
ACETIC ACID / PROPANOIC ACID / : / Carbonic anhydrase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.39 Å
AuthorsManakova, E.N. / Grazulis, S. / Paketuryte-Latve, V. / Vaskevicius, A. / Smirnov, A.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
iNEXT-Discovery871037European Union
Citation
Journal: Elife / Year: 2024
Title: Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX.
Authors: Vaskevicius, A. / Baronas, D. / Leitans, J. / Kvietkauskaite, A. / Ruksenaite, A. / Manakova, E. / Toleikis, Z. / Kaupinis, A. / Kazaks, A. / Gedgaudas, M. / Mickeviciute, A. / ...Authors: Vaskevicius, A. / Baronas, D. / Leitans, J. / Kvietkauskaite, A. / Ruksenaite, A. / Manakova, E. / Toleikis, Z. / Kaupinis, A. / Kazaks, A. / Gedgaudas, M. / Mickeviciute, A. / Juozapaitiene, V. / Schioth, H.B. / Jaudzems, K. / Valius, M. / Tars, K. / Grazulis, S. / Meyer-Almes, F.J. / Matuliene, J. / Zubriene, A. / Dudutiene, V. / Matulis, D.
#1: Journal: Elife / Year: 2024
Title: Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX
Authors: Vaskevicius, A. / Baronas, D. / Leitans, J. / Kvietkauskaite, A. / Ruksenaite, A. / Manakova, E. / Toleikis, Z. / Kaupinis, A. / Kazaks, A. / Gedgaudas, M. / Mickeviciute, A. / ...Authors: Vaskevicius, A. / Baronas, D. / Leitans, J. / Kvietkauskaite, A. / Ruksenaite, A. / Manakova, E. / Toleikis, Z. / Kaupinis, A. / Kazaks, A. / Gedgaudas, M. / Mickeviciute, A. / Juozapaitiene, V. / Schioth, H.B. / Jaudzems, K. / Valius, M. / Tars, K. / Grazulis, S. / Meyer-Almes, F.J. / Matuliene, J. / Zubriene, A. / Dudutiene, V. / Matulis, D.
History
DepositionFeb 21, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Database references / Category: citation / citation_author

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Carbonic anhydrase 1
B: Carbonic anhydrase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,30315
Polymers57,6702
Non-polymers1,63313
Water8,953497
1
A: Carbonic anhydrase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,7909
Polymers28,8351
Non-polymers9548
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Carbonic anhydrase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,5136
Polymers28,8351
Non-polymers6785
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.415, 73.265, 120.570
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Carbonic anhydrase 1 / Carbonate dehydratase I / Carbonic anhydrase B / CAB / Carbonic anhydrase I / CA-I / Cyanamide hydratase CA1


Mass: 28835.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CA1 / Plasmid: pET21A / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P00915, carbonic anhydrase, cyanamide hydratase

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Non-polymers , 8 types, 510 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-PPI / PROPANOIC ACID


Mass: 74.079 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O2
#4: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-VV8 / 3-(cyclooctylamino)-4-ethylsulfonyl-2,5,6-tris(fluoranyl)benzenesulfonamide


Mass: 428.490 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H23F3N2O4S2 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H4O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 497 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.42 Å3/Da / Density % sol: 49.1 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 9 / Details: TrisHCl pH8.5 0.1M, NaCl 0.2M, PEG3350 28% (w/v)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.97552 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 30, 2023
RadiationMonochromator: MONOCHROMATOR: SI 111; LARGE OFFSET MONOCHROMATOR (LOM) : SI 311, SI 511
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97552 Å / Relative weight: 1
ReflectionResolution: 1.39→120.57 Å / Num. obs: 110929 / % possible obs: 98.3 % / Redundancy: 13 % / Biso Wilson estimate: 22.1 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.022 / Rrim(I) all: 0.057 / Χ2: 1.02 / Net I/av σ(I): 20.4 / Net I/σ(I): 13.8
Reflection shellResolution: 1.39→1.41 Å / Redundancy: 4.7 % / Rmerge(I) obs: 2.677 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 3700 / CC1/2: 0.214 / Rpim(I) all: 1.266 / Rrim(I) all: 2.984 / Χ2: 0.99 / % possible all: 67.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSVERSION Jan 10, 2022 BUILT=20220820data reduction
Aimless0.7.4data scaling
MOLREP11.7.02; 29.05.2019phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.39→62.61 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.95 / SU B: 1.611 / SU ML: 0.061 / Cross valid method: THROUGHOUT / ESU R: 0.071 / ESU R Free: 0.074 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.234 10962 9.9 %RANDOM
Rwork0.202 ---
obs0.205 99219 98.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.61 Å2
Baniso -1Baniso -2Baniso -3
1--0.28 Å20 Å20 Å2
2--1.85 Å20 Å2
3----1.57 Å2
Refinement stepCycle: LAST / Resolution: 1.39→62.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4020 0 97 497 4614
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0124337
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8541.6525917
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3145542
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.60123.905210
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.15315684
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2641514
X-RAY DIFFRACTIONr_chiral_restr0.1220.2551
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023378
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.0522.3292113
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.8063.4852654
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.1212.6232224
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.46633.4226730
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.39→1.42 Å
RfactorNum. reflection% reflection
Rfree0.481 475 -
Rwork0.469 5615 -
obs--74.55 %

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