6G5L

Crystal structure of human carbonic anhydrase isozyme XII with 4-chloro-2-(cyclohexylamino)-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.21 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.140 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases.

Zaksauskas, A.Capkauskaite, E.Jezepcikas, L.Linkuviene, V.Kisonaite, M.Smirnov, A.Manakova, E.Grazulis, S.Matulis, D.

(2018) Eur J Med Chem 156: 61-78

  • DOI: https://doi.org/10.1016/j.ejmech.2018.06.059
  • Primary Citation of Related Structures:  
    6G5L, 6G5U, 6G6T, 6G7A

  • PubMed Abstract: 

    Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target.


  • Organizational Affiliation

    Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania.


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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EM5
Query on EM5

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B],
Q [auth C],
T [auth D]
4-chloranyl-2-(cyclohexylamino)-~{N}-(2-hydroxyethyl)-5-sulfamoyl-benzamide
C15 H22 Cl N3 O4 S
MDLHQNNKYAWRKZ-UHFFFAOYSA-N
PEG
Query on PEG

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

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

Download Ideal Coordinates CCD File 
G [auth A]
I [auth A]
L [auth B]
M [auth B]
N [auth B]
G [auth A],
I [auth A],
L [auth B],
M [auth B],
N [auth B],
O [auth B],
R [auth C],
U [auth D],
V [auth D],
W [auth D],
X [auth D],
Z [auth D]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.21 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.140 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.127α = 90
b = 74.235β = 108.64
c = 91.527γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
PDB_EXTRACTdata extraction
Cootmodel building
SCALAdata scaling
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: 2019-03-13
    Type: Initial release
  • Version 1.1: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.2: 2024-11-06
    Changes: Structure summary