3IAI

Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.181 
  • R-Value Work: 0.157 

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This is version 2.2 of the entry. See complete history


Literature

Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX.

Alterio, V.Hilvo, M.Di Fiore, A.Supuran, C.T.Pan, P.Parkkila, S.Scaloni, A.Pastorek, J.Pastorekova, S.Pedone, C.Scozzafava, A.Monti, S.M.De Simone, G.

(2009) Proc Natl Acad Sci U S A 106: 16233-16238

  • DOI: https://doi.org/10.1073/pnas.0908301106
  • Primary Citation of Related Structures:  
    3IAI

  • PubMed Abstract: 

    Carbonic anhydrase (CA) IX is a plasma membrane-associated member of the alpha-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clinically used sulfonamide inhibitor, acetazolamide. The structure reveals a typical alpha-CA fold, which significantly differs from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the PG domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. A correlation between the three-dimensional structure and the physiological role of the enzyme is here suggested, based on the measurement of the pH profile of the catalytic activity for the physiological reaction, CO(2) hydration to bicarbonate and protons. On the basis of the structural differences observed between CA IX and the other membrane-associated alpha-CAs, further prospects for the rational drug design of isozyme-specific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo.


  • Organizational Affiliation

    Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 9
A, B, C, D
257Homo sapiensMutation(s): 1 
Gene Names: CA9G250MN
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q16790 (Homo sapiens)
Explore Q16790 
Go to UniProtKB:  Q16790
PHAROS:  Q16790
GTEx:  ENSG00000107159 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16790
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E, F, G, H
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22768VO
GlyCosmos:  G22768VO
GlyGen:  G22768VO
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AZM
Query on AZM

Download Ideal Coordinates CCD File 
FA [auth C],
J [auth A],
OA [auth D],
V [auth B]
5-ACETAMIDO-1,3,4-THIADIAZOLE-2-SULFONAMIDE
C4 H6 N4 O3 S2
BZKPWHYZMXOIDC-UHFFFAOYSA-N
TRS
Query on TRS

Download Ideal Coordinates CCD File 
CA [auth B],
LA [auth C],
R [auth A],
WA [auth D]
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C4 H12 N O3
LENZDBCJOHFCAS-UHFFFAOYSA-O
PO4
Query on PO4

Download Ideal Coordinates CCD File 
DA [auth B],
MA [auth C],
S [auth A],
T [auth A],
XA [auth D]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
GA [auth C]
HA [auth C]
IA [auth C]
AA [auth B],
BA [auth B],
GA [auth C],
HA [auth C],
IA [auth C],
JA [auth C],
K [auth A],
KA [auth C],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
PA [auth D],
Q [auth A],
QA [auth D],
RA [auth D],
SA [auth D],
TA [auth D],
UA [auth D],
VA [auth D],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
EA [auth C],
I [auth A],
NA [auth D],
U [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AZM BindingDB:  3IAI Ki: min: 0.06, max: 30 (nM) from 12 assay(s)
Kd: min: 0.03, max: 50 (nM) from 12 assay(s)
IC50: min: 2.6, max: 2134 (nM) from 61 assay(s)
PO4 BindingDB:  3IAI Ki: 5.60e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.181 
  • R-Value Work: 0.157 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 144.18α = 90
b = 144.18β = 90
c = 208.89γ = 120
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
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: 2009-09-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2021-10-13
    Changes: Database references, Structure summary
  • Version 2.2: 2023-09-06
    Changes: Data collection, Refinement description