PDBsum entry 6b4d

Lyase

PDB id: 6b4d

Contents

Protein chain

257 a.a.

Ligands

DMS ×2

GOL

53X

Metals

_ZN

Waters ×341

PDB id:

6b4d

Name:

Lyase

Title:

Crystal structure of human carbonic anhydrase ii in complex with a heteroaryl-pyrazole carboxylic acid derivative.

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:

1.20Å R-factor: 0.139 R-free: 0.156

Authors:

C.L.Lomelino,B.P.Mahon,R.Mckenna

Key ref:

R.Cadoni et al. (2017). Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors. ACS Med Chem Lett, 8, 941-946. PubMed id: 28947941

Date:

26-Sep-17 Release date: 07-Feb-18

Supersedes:

5cjl

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

ACS Med Chem Lett 8:941-946 (2017)

PubMed id: 28947941

Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors.

R.Cadoni, N.Pala, C.Lomelino, B.P.Mahon, R.McKenna, R.Dallocchio, A.Dessì, M.Carcelli, D.Rogolino, V.Sanna, M.Rassu, C.Iaccarino, D.Vullo, C.T.Supuran, M.Sechi.

ABSTRACT

We report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, 2c with K_i = 0.21 μM toward hCA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents.