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- PDB-8exc: Human Carbonic Anhydrase II bound tert-butyl (3-(4-(3-((2-(2,6-di... -

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Basic information

Entry
Database: PDB / ID: 8exc
TitleHuman Carbonic Anhydrase II bound tert-butyl (3-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)butoxy)propyl)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-X2U / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 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)R01 AI149444 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 25, 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)30,3204
Polymers29,2891
Non-polymers1,0313
Water4,234235
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)41.986, 41.222, 71.874
Angle α, β, γ (deg.)90.000, 104.211, 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-X2U / N-(3-{4-[3-({2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)propoxy]butoxy}propyl)-4-sulfamoylbenzamide


Mass: 643.708 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H37N5O9S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 321.703 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H5HgO2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.08 Å3/Da / Density % sol: 40.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
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: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1 Å
DetectorType: APEX II CCD / Detector: CCD / Date: Jan 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→34.84 Å / Num. obs: 35992 / % possible obs: 99.4 % / Redundancy: 3.9 % / Biso Wilson estimate: 19.12 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.072 / Rrim(I) all: 0.082 / Net I/σ(I): 11
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.256 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 1798 / CC1/2: 0.928

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
APEXdata reduction
APEXdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Starting model: 4.0E+49 / Resolution: 1.9→34.84 Å / SU ML: 0.2061 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.4186
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2267 3558 9.89 %
Rwork0.1768 32434 -
obs0.1816 35992 97.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.77 Å2
Refinement stepCycle: LAST / Resolution: 1.9→34.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2049 0 56 235 2340
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00812180
X-RAY DIFFRACTIONf_angle_d1.17762961
X-RAY DIFFRACTIONf_chiral_restr0.0636301
X-RAY DIFFRACTIONf_plane_restr0.0073382
X-RAY DIFFRACTIONf_dihedral_angle_d11.5321294
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.27181160.24371037X-RAY DIFFRACTION80.18
1.93-1.950.30321400.22221330X-RAY DIFFRACTION97.61
1.95-1.980.26221340.20881281X-RAY DIFFRACTION97.25
1.98-2.010.29211700.21021302X-RAY DIFFRACTION98.73
2.02-2.050.27071340.20531321X-RAY DIFFRACTION99.52
2.05-2.080.26121380.2041315X-RAY DIFFRACTION98.98
2.08-2.120.24051390.1991286X-RAY DIFFRACTION99.1
2.12-2.160.2711630.21231313X-RAY DIFFRACTION98.27
2.16-2.210.25651490.20091257X-RAY DIFFRACTION97.1
2.21-2.250.29371410.19781317X-RAY DIFFRACTION99.45
2.25-2.310.25961430.19111329X-RAY DIFFRACTION99.19
2.31-2.360.26271500.20161283X-RAY DIFFRACTION97.09
2.36-2.430.27031490.18741319X-RAY DIFFRACTION99.19
2.43-2.50.26261320.20441299X-RAY DIFFRACTION99.1
2.5-2.580.2751500.20061343X-RAY DIFFRACTION99.33
2.58-2.670.23671370.19361271X-RAY DIFFRACTION98.12
2.67-2.780.25791420.18481329X-RAY DIFFRACTION99.86
2.78-2.910.23111460.19031323X-RAY DIFFRACTION99.53
2.91-3.060.26791350.17021275X-RAY DIFFRACTION96.44
3.06-3.250.18031460.17471329X-RAY DIFFRACTION98.33
3.25-3.50.16931430.15771311X-RAY DIFFRACTION99.38
3.5-3.850.19641370.13111322X-RAY DIFFRACTION99.32
3.85-4.40.17341350.13121302X-RAY DIFFRACTION98.63
4.41-5.540.17151440.14281318X-RAY DIFFRACTION99.8
5.56-34.840.19111450.18231322X-RAY DIFFRACTION99.19
Refinement TLS params.Method: refined / Origin x: 12.0734808687 Å / Origin y: -1.84232947979 Å / Origin z: 16.0781817943 Å
111213212223313233
T0.109929128401 Å2-0.0102392116225 Å20.00618161369297 Å2-0.0945811196884 Å20.0102551520471 Å2--0.101128768635 Å2
L1.47760426735 °2-0.433116744078 °20.188654169669 °2-1.90595336678 °20.154142986328 °2--1.90556753597 °2
S-0.0113636823162 Å °0.0228296160798 Å °0.0855143392094 Å °-0.158287492535 Å °0.0483289957864 Å °-0.0365750812672 Å °-0.0779769793616 Å °0.0585917067958 Å °-0.0363098456703 Å °
Refinement TLS groupSelection details: all

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