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PDBsum entry 3ml2
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Lyase/lyase inhibitor
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PDB id
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3ml2
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PDB id:
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| Name: |
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Lyase/lyase inhibitor
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Title:
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Human carbonic anhydsase ii in complex with an aryl sulfonamide inhibitor
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Structure:
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Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, ca-ii, carbonate dehydratase ii, carbonic anhydrasE C, cac. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2, hca2. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.80Å
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R-factor:
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0.189
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R-free:
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0.222
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Authors:
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B.S.Avvaru,J.Wagner,A.H.Robbins,R.Mckenna
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Key ref:
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J.Wagner
et al.
(2010).
Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations.
Bioorg Med Chem Lett,
18,
4873-4878.
PubMed id:
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Date:
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16-Apr-10
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Release date:
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20-Apr-11
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PROCHECK
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Headers
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References
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P00918
(CAH2_HUMAN) -
Carbonic anhydrase 2 from Homo sapiens
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Seq:
Struc:
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260 a.a.
257 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.4.2.1.1
- carbonic anhydrase.
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Reaction:
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hydrogencarbonate + H+ = CO2 + H2O
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hydrogencarbonate
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+
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H(+)
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=
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CO2
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+
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H2O
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Cofactor:
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Zn(2+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Bioorg Med Chem Lett
18:4873-4878
(2010)
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PubMed id:
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Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations.
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J.Wagner,
B.S.Avvaru,
A.H.Robbins,
A.Scozzafava,
C.T.Supuran,
R.McKenna.
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ABSTRACT
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We investigated a series of coumarinyl-substituted aromatic sulfonamides as
inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical
applications, the cytosolic hCA I, and II, and the transmembrane,
tumor-associated hCA IX and XII. Compounds incorporating
7-methoxy-coumarin-4-yl-acetamide-tails and benzenesulfonamide and
benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I
(K(I)s of 73-131nM), effective hCA II inhibition (K(I)s of 9.1-36nM) and less
effective hCA IX and XII inhibition (K(I)s of 55-128nM). Only one compound, the
derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the
coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with
K(I)s of 5.9-14.2nM, although it was less effective as hCA I and II inhibitor
(K(I)s of 36-120nM). An X-ray crystal structure of hCA II in complex with
4-(7-methoxy-coumarin-4-yl-acetamido)-benzenesulfonamide (K(I) of 9.1nM against
hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme
active site by the sulfonamide moiety, and participating in a edge-to-face
stacking with Phe131, in addition to other hydrophobic and hydrophilic
interactions with water molecules and amino acid residues from the active site.
Thus, sulfonamides incorporating coumarin rings have a distinct inhibition
mechanism compared to the coumarins, and may lead to compounds with interesting
inhibition profiles against various alpha-CAs found in mammals or parasites,
such as Plasmodium falciparum.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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F.Carta,
V.Garaj,
A.Maresca,
J.Wagner,
B.S.Avvaru,
A.H.Robbins,
A.Scozzafava,
R.McKenna,
and
C.T.Supuran
(2011).
Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II: Solution and X-ray crystallographic studies.
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Bioorg Med Chem,
19,
3105-3119.
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PDB codes:
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F.Mincione,
F.Benedini,
S.Biondi,
A.Cecchi,
C.Temperini,
G.Formicola,
I.Pacileo,
A.Scozzafava,
E.Masini,
and
C.T.Supuran
(2011).
Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.
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Bioorg Med Chem Lett,
21,
3216-3221.
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PDB code:
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F.Pacchiano,
M.Aggarwal,
B.S.Avvaru,
A.H.Robbins,
A.Scozzafava,
R.McKenna,
and
C.T.Supuran
(2010).
Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.
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Chem Commun (Camb),
46,
8371-8373.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
