PDBsum entry 5gmm

Lyase

PDB id: 5gmm

Contents

Protein chains

257 a.a.

Ligands

949 ×6

Metals

_ZN ×3

Waters ×350

PDB id:

5gmm

Name:

Lyase

Title:

Crystal structure of human carbonic anhydrase i in complex with polmacoxib

Structure:

Carbonic anhydrase 1. Chain: a, b. Synonym: carbonate dehydratase i,carbonic anhydrase b,cab,carbonic anhydrase i,ca-i. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ca1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.178 R-free: 0.227

Authors:

H.T.Kim,K.Y.Hwang

Key ref:

H.T.Kim et al. (2016). Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649). Biochem Biophys Res Commun, 478, 1-6. PubMed id: 27475498 DOI: 10.1016/j.bbrc.2016.07.114

Date:

14-Jul-16 Release date: 24-May-17

Protein chains

P00915  (CAH1_HUMAN) -  Carbonic anhydrase 1 from Homo sapiens

Seq: 261 a.a.

Struc: 257 a.a.

Enzyme reactions

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

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

Added reference

DOI no: 10.1016/j.bbrc.2016.07.114

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

PubMed id: 27475498

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

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

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.