PDBsum entry 4mo8

Lyase/lyase inhibitor

PDB id: 4mo8

Contents

Protein chain

257 a.a.

Ligands

2VQ

Metals

_ZN

Waters ×199

PDB id:

4mo8

Name:

Lyase/lyase inhibitor

Title:

The crystal structure of the human carbonic anhydrase ii in complex with n-[2-(2-methyl-5-nitro-1h-imidazol-1-yl)ethyl]sulfamide

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: 562

Resolution:

1.85Å R-factor: 0.163 R-free: 0.196

Authors:

V.Alterio,G.De Simone

Key ref:

M.Rami et al. (2013). Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates. J Med Chem, 56, 8512-8520. PubMed id: 24128000 DOI: 10.1021/jm4009532

Date:

11-Sep-13 Release date: 30-Oct-13

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 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: 10.1021/jm4009532

J Med Chem 56:8512-8520 (2013)

PubMed id: 24128000

Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates.

M.Rami, L.Dubois, N.K.Parvathaneni, V.Alterio, S.J.van Kuijk, S.M.Monti, P.Lambin, G.De Simone, C.T.Supuran, J.Y.Winum.

ABSTRACT

A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes.