5E2N

Crystal structure of human carbonic anhydrase isozyme XIII with 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.180 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Intrinsic Thermodynamics and Structures of 2,4- and 3,4-Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases.

Zubriene, A.Smirnov, A.Dudutiene, V.Timm, D.D.Matuliene, J.Michailoviene, V.Zaksauskas, A.Manakova, E.Grazulis, S.Matulis, D.

(2017) ChemMedChem 12: 161-176

  • DOI: https://doi.org/10.1002/cmdc.201600509
  • Primary Citation of Related Structures:  
    5DOG, 5DOH, 5DRS, 5E2M, 5E2N, 5EHE

  • PubMed Abstract: 

    The goal of rational drug design is to understand structure-thermodynamics correlations in order to predict the chemical structure of a drug that would exhibit excellent affinity and selectivity for a target protein. In this study we explored the contribution of added functionalities of benzenesulfonamide inhibitors to the intrinsic binding affinity, enthalpy, and entropy for recombinant human carbonic anhydrases (CA) CA I, CA II, CA VII, CA IX, CA XII, and CA XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from -90 to +10 kJ mol -1 , and are compensated by a similar opposing entropy contribution. The intrinsic parameters of binding were determined by subtracting the linked protonation reactions. The sulfonamide group pK a values of the compounds were measured spectrophotometrically, and the protonation enthalpies were measured by isothermal titration calorimetry (ITC). Herein we describe the development of meta- or ortho-substituted fluorinated benzenesulfonamides toward the highly potent compound 10 h, which exhibits an observed dissociation constant value of 43 pm and an intrinsic dissociation constant value of 1.1 pm toward CA IX, an anticancer target that is highly overexpressed in various tumors. Fluorescence thermal shift assays, ITC, and X-ray crystallography were all applied in this work.


  • Organizational Affiliation

    Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 13
A, B
263Homo sapiensMutation(s): 0 
Gene Names: CA13
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q8N1Q1 (Homo sapiens)
Explore Q8N1Q1 
Go to UniProtKB:  Q8N1Q1
PHAROS:  Q8N1Q1
GTEx:  ENSG00000185015 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8N1Q1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V14
Query on V14

Download Ideal Coordinates CCD File 
I [auth A],
O [auth B]
3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide
C16 H23 F3 N2 O5 S2
HFJJAVOBUVMVFQ-UHFFFAOYSA-N
CIT
Query on CIT

Download Ideal Coordinates CCD File 
K [auth B]CITRIC ACID
C6 H8 O7
KRKNYBCHXYNGOX-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
D [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
L [auth B]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
L [auth B],
M [auth B],
N [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
V14 BindingDB:  5E2N Kd: min: 2, max: 42 (nM) from 5 assay(s)
Binding MOAD:  5E2N Kd: 0.29 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.087α = 90
b = 57.597β = 90
c = 159.749γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PDB_EXTRACTdata extraction
REFMACrefinement
XDSdata reduction
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: 2016-10-05
    Type: Initial release
  • Version 1.1: 2017-01-18
    Changes: Database references
  • Version 1.2: 2017-02-01
    Changes: Database references
  • Version 1.3: 2018-03-07
    Changes: Data collection
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Refinement description