PDBsum entry 4bf6

Lyase

PDB id: 4bf6

Contents

Protein chain

257 a.a.

Ligands

X0Q

GOL

Metals

_ZN

Waters ×296

PDB id:

4bf6

Name:

Lyase

Title:

Three dimensional structure of human carbonic anhydrase ii in complex with 5-(1-(3-cyanophenyl)-1h-1,2,3-triazol-4-yl)thiophene-2- 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. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.82Å R-factor: 0.148 R-free: 0.202

Authors:

K.Tars,J.Leitans,R.Zalubovskis

Key ref:

J.Leitans et al. (2013). 5-Substituted-(1,2,3-triazol-4-yl)thiophene-2-sulfonamides strongly inhibit human carbonic anhydrases I, II, IX and XII: solution and X-ray crystallographic studies. Bioorg Med Chem Lett, 21, 5130-5138. PubMed id: 23859774 DOI: 10.1016/j.bmc.2013.06.041

Date:

15-Mar-13 Release date: 22-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.2013.06.041

Bioorg Med Chem Lett 21:5130-5138 (2013)

PubMed id: 23859774

5-Substituted-(1,2,3-triazol-4-yl)thiophene-2-sulfonamides strongly inhibit human carbonic anhydrases I, II, IX and XII: solution and X-ray crystallographic studies.

J.Leitans, A.Sprudza, M.Tanc, I.Vozny, R.Zalubovskis, K.Tars, C.T.Supuran.

ABSTRACT

We report here a series of 2-thiophene-sulfonamides incorporating 1-substituted aryl-1,2,3-triazolyl moieties, prepared by click chemistry from 5-ethynylthiophene-2-sulfonamide and substituted aryl azides. The new sulfonamides were investigated as inhibitors of the zinc metalloenzyme CA (EC 4.2.1.1), and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated ones hCA IX and XII: The new compounds were medium-weak hCA I inhibitors (KIs in the range of 224-7544nM), but were compactly, highly effective, low nanomolar hCA II inhibitors (KIs of 2.2-7.7nM). The tumor-associated hCA IX was inhibited with KIs ranging between 5.4 and 811nM, whereas hCA XII with inhibition constants in the range of 3.4-239nM. The X-ray crystal structure of the adducts of two such compounds bound to hCA II (one incorporating 1-naphthyl, the other one 3-cyanophenyl moieties) evidenced the reasons of the high affinity for hCA II. Highly favorable, predominantly hydrophobic interactions between the sulfonamide scaffold and the hCA II active site were responsible for the binding, in addition to the coordination of the sulfamoyl moiety to the zinc ion. The tails of the two inhibitors adopted very diverse orientations when bound to the active site, with the naphthyltriazolyl moiety orientated towards the hydrophobic half of the active site, and the 3-cyanophenyl one pointing towards the hydrophilic half. These data may be used for the structure-based drug design of even more effective hCA II inhibitors, with potential use as antiglaucoma agents or as diuretics.