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- PDB-8exg: Human Carbonic Anhydrase II bound N-(2-(2-((2-(2,6-dioxopiperidin... -

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Basic information

Entry
Database: PDB / ID: 8exg
TitleHuman Carbonic Anhydrase II bound N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)-4-sulfamoylbenzamide
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 activity / cyanamide hydratase / arylesterase activity / regulation of chloride transport / Reversible hydration of carbon dioxide / morphogenesis of an epithelium ...positive regulation of cellular pH reduction / positive regulation of dipeptide transmembrane transport / regulation of monoatomic anion transport / secretion / cyanamide hydratase activity / cyanamide hydratase / arylesterase activity / regulation of chloride transport / Reversible hydration of carbon dioxide / morphogenesis of an epithelium / angiotensin-activated signaling pathway / regulation of intracellular pH / positive regulation of synaptic transmission, GABAergic / 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 / apical part of cell / myelin sheath / extracellular exosome / zinc ion binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Carbonic Anhydrase II / Alpha carbonic anhydrase / 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 ...Carbonic Anhydrase II / Alpha carbonic anhydrase / 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 / Roll / Alpha Beta
Similarity search - Domain/homology
MERCURIBENZOIC ACID / Chem-X38 / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.99 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

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Assembly

Deposited unit
A: Carbonic anhydrase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2824
Polymers29,2891
Non-polymers9933
Water2,522140
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)42.207, 41.659, 71.948
Angle α, β, γ (deg.)90.000, 104.268, 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-X38 / (4S)-5-amino-4-{1,3-dioxo-4-[(2-{2-[2-(4-sulfamoylbenzamido)ethoxy]ethoxy}ethyl)amino]-1,3-dihydro-2H-isoindol-2-yl}-5-oxopentanoic acid


Mass: 605.617 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H31N5O10S / Feature type: SUBJECT OF INVESTIGATION
#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.: 140 / 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: 2.09 Å3/Da / Density % sol: 41.23 %
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: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1 Å
DetectorType: APEX II CCD / Detector: CCD / Date: Feb 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.13→40.91 Å / Num. obs: 32102 / % possible obs: 95.1 % / Redundancy: 5.8 % / Biso Wilson estimate: 17.91 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.091 / Rrim(I) all: 0.1 / Net I/σ(I): 12
Reflection shellResolution: 1.13→1.17 Å / Rmerge(I) obs: 0.605 / Mean I/σ(I) obs: 2 / Num. unique obs: 6527 / CC1/2: 0.748 / Rrim(I) all: 0.736

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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: 1.99→40.91 Å / SU ML: 0.2043 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.8476
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2233 3200 9.97 %
Rwork0.1872 28902 -
obs0.1907 32102 99.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.67 Å2
Refinement stepCycle: LAST / Resolution: 1.99→40.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2049 0 53 140 2242
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00572176
X-RAY DIFFRACTIONf_angle_d0.87392956
X-RAY DIFFRACTIONf_chiral_restr0.0542301
X-RAY DIFFRACTIONf_plane_restr0.0072382
X-RAY DIFFRACTIONf_dihedral_angle_d17.3423289
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.99-2.020.27151290.26341141X-RAY DIFFRACTION90.65
2.02-2.060.2581260.24631236X-RAY DIFFRACTION98.34
2.06-2.090.30591610.23661228X-RAY DIFFRACTION98.93
2.09-2.130.25271180.20731276X-RAY DIFFRACTION98.94
2.13-2.160.25891580.22611226X-RAY DIFFRACTION99.14
2.16-2.210.21031250.20781263X-RAY DIFFRACTION99.28
2.21-2.250.2681330.20991279X-RAY DIFFRACTION99.58
2.25-2.30.24061470.19211280X-RAY DIFFRACTION100
2.3-2.350.23811410.19841257X-RAY DIFFRACTION100
2.35-2.410.2441610.1881228X-RAY DIFFRACTION100
2.41-2.480.26281150.19531338X-RAY DIFFRACTION100
2.48-2.550.29751560.1961192X-RAY DIFFRACTION100
2.55-2.630.23921230.18831303X-RAY DIFFRACTION100
2.63-2.730.19521540.17541231X-RAY DIFFRACTION100
2.73-2.840.2351320.17771312X-RAY DIFFRACTION100
2.84-2.970.20261560.18011264X-RAY DIFFRACTION100
2.97-3.120.21061390.16781236X-RAY DIFFRACTION99.93
3.12-3.320.19991360.16441260X-RAY DIFFRACTION99.93
3.32-3.570.17811330.1681281X-RAY DIFFRACTION100
3.57-3.930.21121410.15021264X-RAY DIFFRACTION100
3.93-4.50.18791430.15531268X-RAY DIFFRACTION100
4.5-5.670.18791370.19291261X-RAY DIFFRACTION100
5.67-40.910.23821360.21571278X-RAY DIFFRACTION100
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)
13.932260760520.02200602319620.9334821707032.915418515441.065197008474.09019991353-0.07074537206760.0475465444489-0.0386599049891-0.114826682508-0.109945418281-0.3955094810050.2358395165830.4260209701610.1626968416850.1027453522610.01329878379370.03376276886640.1250225867410.03256921780490.19482664662829.738430026-3.0791770991616.4933721211
21.45853346854-0.3871157783270.003745062548131.70055908172-0.2635169445542.24816982469-0.06053119114290.02742671234440.109775917670.02629691239370.1141818665710.0703535049982-0.263769328658-0.0980974466757-0.03938332330270.090022107095-0.0178515348656-0.006347385760320.08178393743410.005491326112810.09846391019237.374086550512.908387161218.1996701841
31.955469480240.2515010943680.02664709396670.5618082402620.2140486378154.26127289742-0.02501277673460.0567517746272-0.3075975681190.03893986212060.0536936165936-0.006213958351840.4940404105730.0308748456757-0.04847672207790.1434448243440.0005784927253040.01278741732950.05094819084470.006818357739240.12492773150913.2974140751-14.609212046919.2262864192
41.31481514529-0.06330512889690.02993457518411.28902289116-0.04039050913341.75207699079-0.01965660780080.08761741845070.0543528128808-0.1758569838390.03632022549390.09019132298190.00129462988875-0.0825283364502-0.01755843842140.0816097199031-0.000945447725743-0.01299579265290.07185965278260.005994939629210.06831148892348.1706136511-0.093010624046914.7252556703
54.140292985721.21369918184-1.086938812362.32927876053-1.130554329112.2790033515-0.0198840740830.588957152558-0.0565252882638-0.5575539712790.0602039793759-0.301132831318-0.001624003825860.0777004456595-0.08343701266720.277304395470.04664469938540.04071496697670.186670727156-0.01710872214510.097439610029216.4426831419-10.65076612030.838658303219
62.075576351770.182054759480.4639237183881.927268470280.1569310839531.000168996080.060534108348-0.349541055113-0.07453225770870.1614185665450.0402716232021-0.169069850339-0.07005933433480.106790386093-0.05330301731150.09635535043930.00194488645836-0.01241063197860.07329158596650.01806290183530.072578929705515.623786624-6.7366808213923.9620579014
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 24 )4 - 241 - 21
22chain 'A' and (resid 25 through 97 )25 - 9722 - 94
33chain 'A' and (resid 98 through 115 )98 - 11595 - 112
44chain 'A' and (resid 116 through 219 )116 - 219113 - 215
55chain 'A' and (resid 220 through 238 )220 - 238216 - 234
66chain 'A' and (resid 239 through 261 )239 - 261235 - 257

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