5GMM

Crystal structure of human Carbonic anhydrase I in complex with polmacoxib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649).

Kim, H.T.Cha, H.Hwang, K.Y.

(2016) Biochem Biophys Res Commun 478: 1-6

  • DOI: https://doi.org/10.1016/j.bbrc.2016.07.114
  • Primary Citation of Related Structures:  
    5GMM, 5GMN

  • PubMed Abstract: 

    Polmacoxib is not only a selective COX-2 inhibitor but also a potent inhibitor of carbonic anhydrases (CAs). Both CA I and CA II are highly expressed in the GI tract and kidneys, organs that are also thought to be the sites at which selective COX-2 inhibitors show their side effects. By inhibition assays, we show that both CA I and CA II are strongly inhibited by polmacoxib, while CA II also demonstrates direct competition with COX-2. To understand, at the molecular level, how polmacoxib interacts with CA I and II, we solved the first crystal structures of CA I and CA II in complex with polmacoxib, at 2.0 Å and 1.8 Å, respectively. Interestingly, three polmacoxib molecules bind to the active site of CA I, whereas only one molecule binds CA II. In the active site, the three molecules of polmacoxib organize itself along hydrophobic interaction as "stack-on-formation", and fully occupy a cone-shaped active pocket in CA I. The binding mode of polmacoxib to CA II was found different than its binding to celecoxib and valdecoxib. Our results provide structural insight into inhibition of CA I and CA II by polmacoxib, to assess its potential clinical efficacy.


  • Organizational Affiliation

    Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul, 136-701, Republic of Korea.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 1
A, B
261Homo sapiensMutation(s): 0 
Gene Names: CA1
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00915 (Homo sapiens)
Explore P00915 
Go to UniProtKB:  P00915
PHAROS:  P00915
GTEx:  ENSG00000133742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00915
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
949
Query on 949

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
I [auth B]
J [auth B]
D [auth A],
E [auth A],
F [auth A],
I [auth B],
J [auth B],
K [auth B]
4-[3-(3-fluorophenyl)-5,5-dimethyl-4-oxidanylidene-furan-2-yl]benzenesulfonamide
C18 H16 F N O4 S
IJWPAFMIFNSIGD-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B],
H [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
949 Binding MOAD:  5GMM Kd: 2.91e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.265α = 90
b = 87.953β = 90
c = 142.58γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-24
    Type: Initial release
  • Version 1.1: 2018-06-20
    Changes: Data collection, Structure summary
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description