PDBsum entry 4itp

Lyase/lyase inhibitor

PDB id: 4itp

Contents

Protein chain

257 a.a.

Ligands

GOL ×5

1GD

DMS

Metals

_ZN

Waters ×219

PDB id:

4itp

Name:

Lyase/lyase inhibitor

Title:

Structure of human carbonic anhydrase ii bound to a benzene sulfonamide

Structure:

Carbonic anhydrase 2. Chain: a. Synonym: carbonate dehydratase ii, carbonic anhydrasE C, cac, carbonic anhydrase ii, ca-ii. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2. Expressed in: escherichia coli. Expression_system_taxid: 469008

Resolution:

1.70Å R-factor: 0.155 R-free: 0.191

Authors:

S.Biswas,R.Mckenna

Key ref:

O.Güzel-Akdemir et al. (2013). Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition. Bioorg Med Chem Lett, 21, 6674-6680. PubMed id: 24012377 DOI: 10.1016/j.bmc.2013.08.011

Date:

18-Jan-13 Release date: 01-Jan-14

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 a.a.

Struc: 257 a.a.

Enzyme reactions

• Enzyme class 2: E.C.4.2.1.1 - carbonic anhydrase.
• Reaction: hydrogencarbonate + H⁺ = CO2 + H2O
• Cofactor: Zn(2+)
• Enzyme class 3: E.C.4.2.1.69 - cyanamide hydratase.
• Reaction: urea = cyanamide + H2O

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmc.2013.08.011

Bioorg Med Chem Lett 21:6674-6680 (2013)

PubMed id: 24012377

Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition.

O.Güzel-Akdemir, S.Biswas, K.Lastra, R.McKenna, C.T.Supuran.

ABSTRACT

The crystal structure of 4-phenylacetamidomethyl-benzenesulfonamide (4ITP) bound to human carbonic anhydrase (hCA, EC 4.2.1.1) II is reported. 4ITP is a medium potency hCA I and II inhibitor (KIs of 54-75nM), a strong mitochondrial CA VA/VB inhibitor (KIs of 8.3-8.6nM) and a weak transmembrane CA inhibitor (KIs of 136-212nM against hCA IX and XII). This elongated compound binds in an extended conformation to hCA II, with its tail lying towards the hydrophobic half of the active site whereas the sulfonamide moiety coordinates the zinc ion. The present structure was compared to that of structurally related aromatic sulfonamides, such as 4-phenylacetamido-benzene-sulfonamide (3OYS), 4-(2-mercaptophenylacetamido)-benzene-sulfonamide (2HD6) and 4-(3-nitrophenyl)-ureido-benzenesulfonamide (3N2P). Homology models of the hCA I, VA, VB, IX and XII structures were build which afforded an understanding of the amino acids involved in the binding of these compounds to these isoforms. The main conclusion of the study is that the orientation of the tail moiety and the presence of flexible linkers as well polar groups in it, strongly influence the potency and the selectivity of the sulfonamides for the inhibition of cytosolic, mitochondrial or transmembrane CA isoforms.