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- PDB-8eyl: Human Carbonic Anhydrase II with Tert-butyl (2-(2-((2-(2,6-dioxop... -

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Basic information

Entry
Database: PDB / ID: 8eyl
TitleHuman Carbonic Anhydrase II with Tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamate
ComponentsCarbonic anhydrase 2
KeywordsLYASE / targeted protein degrader / PROTAC / metalloenzyme
Function / homology
Function and homology information


positive regulation of cellular pH reduction / positive regulation of dipeptide transmembrane transport / regulation of monoatomic anion transport / secretion / cyanamide hydratase / cyanamide hydratase activity / arylesterase activity / regulation of chloride transport / Reversible hydration of carbon dioxide / angiotensin-activated signaling pathway ...positive regulation of cellular pH reduction / positive regulation of dipeptide transmembrane transport / regulation of monoatomic anion transport / secretion / cyanamide hydratase / cyanamide hydratase activity / arylesterase activity / regulation of chloride transport / Reversible hydration of carbon dioxide / angiotensin-activated signaling pathway / positive regulation of synaptic transmission, GABAergic / morphogenesis of an epithelium / regulation of intracellular pH / carbonic anhydrase / carbonate dehydratase activity / carbon dioxide transport / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen / neuron cellular homeostasis / one-carbon metabolic process / apical part of cell / myelin sheath / zinc ion binding / extracellular exosome / plasma membrane / cytoplasm / cytosol
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
MERCURIBENZOIC ACID / Chem-X5F / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.18 Å
AuthorsKohlbrand, A.J. / O'Herin, C.B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Development of Human Carbonic Anhydrase II Heterobifunctional Degraders.
Authors: O'Herin, C.B. / Moriuchi, Y.W. / Bemis, T.A. / Kohlbrand, A.J. / Burkart, M.D. / Cohen, S.M.
History
DepositionOct 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 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

Downloads & links

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Assembly

Deposited unit
A: Carbonic anhydrase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,8355
Polymers29,2891
Non-polymers1,5464
Water3,945219
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.872, 41.036, 71.269
Angle α, β, γ (deg.)90.000, 103.954, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Carbonic anhydrase 2 / Carbonate dehydratase II / Carbonic anhydrase C / CAC / Carbonic anhydrase II / CA-II


Mass: 29289.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CA2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00918, carbonic anhydrase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MBO / MERCURIBENZOIC ACID


Mass: 321.703 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H5HgO2
#4: Chemical ChemComp-X5F / 2-[[(2~{R})-1-azanyl-5-oxidanyl-1,5-bis(oxidanylidene)pentan-2-yl]carbamoyl]-6-[2-[2-[(4-sulfamoylphenyl)carbonylamino]ethoxy]ethylamino]benzoic acid


Mass: 579.580 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29N5O10S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / 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: 2.03 Å3/Da / Density % sol: 39.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 2.6-3.0 M Ammonium sulfate in 50 mM Tris-Sulfate (pH 8)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.18→40.64 Å / Num. obs: 71372 / % possible obs: 99 % / Redundancy: 4.1 % / Biso Wilson estimate: 15.01 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.08 / Rrim(I) all: 0.091 / Net I/σ(I): 15
Reflection shellResolution: 1.18→1.21 Å / Num. unique obs: 6011 / CC1/2: 0.991

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Starting model: 4.0E+49 / Resolution: 1.18→40.64 Å / SU ML: 0.1122 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.8918
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1932 1994 2.79 %
Rwork0.1815 69378 -
obs0.1818 71372 91.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.84 Å2
Refinement stepCycle: LAST / Resolution: 1.18→40.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2049 0 65 219 2333
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00822187
X-RAY DIFFRACTIONf_angle_d1.08682971
X-RAY DIFFRACTIONf_chiral_restr0.0935301
X-RAY DIFFRACTIONf_plane_restr0.0085386
X-RAY DIFFRACTIONf_dihedral_angle_d17.8851291
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.18-1.210.29550.34132146X-RAY DIFFRACTION39.65
1.21-1.240.29931120.2783550X-RAY DIFFRACTION66.04
1.24-1.270.28841260.27084369X-RAY DIFFRACTION80.51
1.27-1.320.25721370.25615125X-RAY DIFFRACTION95.07
1.32-1.360.25641610.25475376X-RAY DIFFRACTION99.96
1.36-1.420.2931520.23895397X-RAY DIFFRACTION99.91
1.42-1.480.23171550.22935374X-RAY DIFFRACTION99.87
1.48-1.560.21471560.21845419X-RAY DIFFRACTION99.93
1.56-1.660.21151600.2095397X-RAY DIFFRACTION99.84
1.66-1.790.19091560.20135433X-RAY DIFFRACTION99.8
1.79-1.970.21321580.18395397X-RAY DIFFRACTION99.57
1.97-2.250.19451530.17835412X-RAY DIFFRACTION99.39
2.25-2.830.17961540.17475454X-RAY DIFFRACTION99.5
2.83-40.640.16251590.14845529X-RAY DIFFRACTION98.99
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)
18.89324075484-1.641869840081.344317673253.680667895622.504149419447.0828479497-0.06522324302780.19488100572-0.200753915213-0.367016525833-0.0764573766528-0.6327945282790.1151478574270.3023010848050.1443006381790.1381962893210.002995021739070.07835832851290.1974858440790.02623933534910.23073656486229.9526434116-4.4937785374414.5394694695
24.045741536331.03396328481-2.495132777652.57634922928-1.225046891593.70296792078-0.127871160851-0.362917356743-0.04434167575010.1948949930470.111944781571-0.1879982825940.06977633320170.1828978171690.02901465757490.1691473756950.044064132431-0.03518288439320.215343684278-0.01190043614750.10668134721218.086898305-3.7315458575528.8941635957
32.03848520417-1.27827066068-0.268394912542.58012204712-0.5777365631213.27039316690.108243932862-0.1151956011510.0983163579595-0.2127861182810.05289976720780.176627970567-0.427658525416-0.103753403921-0.1962664912020.174908374652-0.0599501589966-0.05575037478080.127509000063-0.01217896642760.1165659234175.718627450613.2628256889714.0659462823
41.67311473894-1.15801656296-0.1259385797814.590452151450.3302866303671.67656674611-0.0187538677964-0.02709900365410.0114910487286-0.1778716719940.03253798194380.207017901967-0.0681134144208-0.015399065602-0.02514778379440.0870150560099-0.0263995434025-0.01844406501120.118844084203-0.001311890807330.07245717365448.48023238709-1.112459545217.0974137982
51.075786120890.7916969048570.3563994196416.006100493131.598021090781.84283950728-0.0227980846441-0.04027316633460.0738663717361-0.1630573373560.04431004808630.0693117214845-0.139079477240.0706605712413-0.01114242727390.1331396672990.00326608655704-0.0007768375019450.135703877065-0.0009640865324490.0768769111399.520767107174.0311079444317.8702387981
64.212255948133.90922181035-5.936924451795.76982484082-4.66094836798.89603661724-0.3384345527530.7045145024-0.14418543876-0.8683920978980.2432484446620.3235886913470.106949743954-0.5203643581070.1096067210520.337040912705-0.0159922502657-0.08753514960290.19017000811-0.01776968734370.1660883114455.30660045029-6.427384684130.227366113837
71.107498356650.0835449644223-0.005813659315581.492503809140.2534253413531.11533888541-0.01445827537180.05422784103260.0123330020211-0.2191334997760.01902365848780.131056696057-0.0495050803048-0.0554378666237-0.01994918279760.1254929197750.0123706648787-0.01988479695020.09586821361270.01221276430890.06422219832147.93701743401-1.6585187009415.5602633349
85.985092005790.682830355718-2.473492071162.93521394124-1.754108391683.79738317857-0.1060260211270.44649104043-0.102114075673-0.5693931852050.0946546208765-0.2217101401890.01749891338280.3500657639350.007546873957850.316423445499-0.0309662788160.03611343733760.227411350271-0.0362829045010.094030103890916.4601675354-10.92011282370.863228314901
93.22952703222-0.477557714173-0.4998600307642.642337611191.159807565453.58799228621-0.0631419924758-0.365986966526-0.03442700342460.1455539861420.192887096367-0.0665753681958-0.02992647223650.214007599356-0.1472899375010.1129603603330.0115583200128-0.00600869889910.0830759362490.04230205005740.065527737043615.6699394869-6.4819760900823.900844934
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 4 through 19 )4 - 191 - 16
22chain 'A' and (resid 20 through 39 )20 - 3917 - 36
33chain 'A' and (resid 40 through 70 )40 - 7037 - 67
44chain 'A' and (resid 71 through 115 )71 - 11568 - 112
55chain 'A' and (resid 116 through 154 )116 - 154113 - 150
66chain 'A' and (resid 155 through 167 )155 - 167151 - 163
77chain 'A' and (resid 168 through 219 )168 - 219164 - 215
88chain 'A' and (resid 220 through 238 )220 - 238216 - 234
99chain 'A' and (resid 239 through 261 )239 - 261235 - 257

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