PDBsum entry 3f4x

Lyase

PDB id: 3f4x

Contents

Protein chain

256 a.a. *

Ligands

KLT

Metals

_ZN

_HG

Waters ×190

* Residue conservation analysis

PDB id:

3f4x

Name:

Lyase

Title:

Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide x-ray crystal structures in adducts with isozyme ii: when three water molecules make the difference

Structure:

Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, ca-ii, carbonate dehydratase ii, carbonic anhydrasE C, cac. Ec: 4.2.1.1

Source:

Homo sapiens. Human. Organism_taxid: 9606

Resolution:

1.90Å R-factor: 0.202 R-free: 0.252

Authors:

C.Temperini,A.Cecchi,A.Scozzafava,C.T.Supuran

Key ref:

C.Temperini et al. (2009). Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide X-ray crystal structures in adducts with isozyme II: when three water molecules and the keto-enol tautomerism make the difference. J Med Chem, 52, 322-328. PubMed id: 19115843

Date:

03-Nov-08 Release date: 17-Mar-09

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 a.a.

Struc: 256 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

J Med Chem 52:322-328 (2009)

PubMed id: 19115843

Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide X-ray crystal structures in adducts with isozyme II: when three water molecules and the keto-enol tautomerism make the difference.

C.Temperini, A.Cecchi, A.Scozzafava, C.T.Supuran.

ABSTRACT

Thiazide diuretics inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a different profile as compared to classical inhibitors. Acting as moderate-weak inhibitors of CA II and CA I, chlorthalidone and indapamide considerably inhibit other isozymes among the 16 CAs present in vertebrates. These compounds show a different behavior against CAs I and II, with chlorthalidone being 18.3 times more potent against CA II and 150 times more potent against CA I, as compared to indapamide. In the X-ray crystal structures of the CA II-chlorthalidone adduct three active site water molecules interacting with the inhibitor scaffold were observed that lack in the corresponding indapamide adduct. Chlorthalidone bound within the active site is in an enolic tautomeric form, with the OH moiety participating in two strong hydrogen bonds with Asn67 and a water molecule. This binding mode may be exploited for designing better CA II inhibitors.