4WW8

Crystal structure of human carbonic anhydrase isozyme XII with 4-Propylthiobenzenesulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Intrinsic thermodynamics of 4-substituted-2,3,5,6-tetrafluorobenzenesulfonamide binding to carbonic anhydrases by isothermal titration calorimetry.

Zubriene, A.Smirnoviene, J.Smirnov, A.Morkunaite, V.Michailoviene, V.Jachno, J.Juozapaitiene, V.Norvaisas, P.Manakova, E.Grazulis, S.Matulis, D.

(2015) Biophys Chem 205: 51-65

  • DOI: https://doi.org/10.1016/j.bpc.2015.05.009
  • Primary Citation of Related Structures:  
    4WR7, 4WUP, 4WUQ, 4WW6, 4WW8

  • PubMed Abstract: 

    Para substituted tetrafluorobenzenesulfonamides bind to carbonic anhydrases (CAs) extremely tightly and exhibit some of the strongest known protein-small ligand interactions, reaching an intrinsic affinity of 2 pM as determined by displacement isothermal titration calorimetry (ITC). The enthalpy and entropy of binding to five CA isoforms were measured by ITC in two buffers of different protonation enthalpies. The pKa values of compound sulfonamide groups were measured potentiometrically and spectrophotometrically, and enthalpies of protonation were measured by ITC in order to evaluate the proton linkage contributions to the observed binding thermodynamics. Intrinsic means the affinity of a sulfonamide anion for the Zn bound water form of CAs. Fluorination of the benzene ring significantly enhanced the observed affinities as it increased the fraction of deprotonated ligand while having little impact on intrinsic affinities. Intrinsic enthalpy contributions to the binding affinity were dominant over entropy and were more exothermic for CA I than for other CA isoforms. Thermodynamic measurements together with the X-ray crystallographic structures of protein-ligand complexes enabled analysis of structure-activity relationships in this enzyme ligand system.


  • Organizational Affiliation

    Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius LT-02241, Lithuania. Electronic address: astzu@ibt.lt.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 12
A, B, C, D
263Homo sapiensMutation(s): 0 
Gene Names: CA12
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for O43570 (Homo sapiens)
Explore O43570 
Go to UniProtKB:  O43570
PHAROS:  O43570
GTEx:  ENSG00000074410 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO43570
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VD9
Query on VD9

Download Ideal Coordinates CCD File 
I [auth A],
Q [auth B],
U [auth C],
Y [auth D]
4-(propylsulfanyl)benzenesulfonamide
C9 H13 N O2 S2
QFWWUTSCPNTDPO-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
J [auth B],
R [auth C],
V [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
K [auth B]
L [auth B]
F [auth A],
G [auth A],
H [auth A],
K [auth B],
L [auth B],
M [auth B],
N [auth B],
O [auth B],
P [auth B],
S [auth C],
T [auth C],
W [auth D],
X [auth D]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
VD9 BindingDB:  4WW8 Kd: 400 (nM) from 1 assay(s)
Binding MOAD:  4WW8 Kd: 0.07 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.313α = 90
b = 74.26β = 108.66
c = 91.57γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
PDB_EXTRACTdata extraction
SCALAdata scaling
REFMACrefinement
Cootmodel building
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-01
    Type: Initial release
  • Version 1.1: 2018-03-07
    Changes: Data collection
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description