PDBsum entry 4kv0

Lyase/lyase inhibitor

PDB id: 4kv0

Contents

Protein chain

257 a.a.

Ligands

GOL

BME

MB7

Metals

_ZN

Waters ×337

PDB id:

4kv0

Name:

Lyase/lyase inhibitor

Title:

Crystal structure of human carbonic anhydrase ii in complex with the 5-(3-tosylureido)pyridine-2-sulfonamide inhibitor

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: 511693.

Resolution:

1.55Å R-factor: 0.159 R-free: 0.179

Authors:

M.Ferraroni

Key ref:

M.Bozdag et al. (2014). Combining the tail and the ring approaches for obtaining potent and isoform-selective carbonic anhydrase inhibitors: solution and X-ray crystallographic studies. Bioorg Med Chem Lett, 22, 334-340. PubMed id: 24300919 DOI: 10.1016/j.bmc.2013.11.016

Date:

22-May-13 Release date: 25-Jun-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

hydrogencarbonate + H(+) = CO2 (Bound ligand (Het Group name = BME) matches with 40.00% similarity) + 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.2013.11.016

Bioorg Med Chem Lett 22:334-340 (2014)

PubMed id: 24300919

Combining the tail and the ring approaches for obtaining potent and isoform-selective carbonic anhydrase inhibitors: solution and X-ray crystallographic studies.

M.Bozdag, M.Ferraroni, E.Nuti, D.Vullo, A.Rossello, F.Carta, A.Scozzafava, C.T.Supuran.

ABSTRACT

5-(3-Tosylureido)pyridine-2-sulfonamide and 4-tosylureido-benzenesulfonamide (ts-SA) only differ by the substitution of a CH by a nitrogen atom, but they have very different inhibitory properties against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). By means of X-ray crystallography on the human CA II adducts of the two compounds these differences have been rationalized. As all sulfonamides, the two compounds bind in deprotonated form to the Zn(II) ion from the enzyme active site and their organic scaffolds extend throughout the cavity, participating in many interactions with amino acid residues and water molecules. However the pyridine derivative undergoes a tilt of the heterocyclic ring compared to the benzene analog, which leads to a very different orientation of the two scaffolds when bound to the enzyme. This tilt also leads to a clash between a carbon atom from the pyridine ring of the first inhibitor and the OH moiety of Thr200, leading to less effective inhibitory properties of the pyridine versus the benzene sulfonamide derivative. Indeed, ts-SA is a promiscuous, low nanomolar inhibitor of 7 out of 10 human (h) CA isoforms, whereas the pyridine sulfonamide is a low nanomolar inhibitor only of the tumor-associated hCA IX and XII, being less effective against other 9 isoforms. Thus, a difference of one atom (N vs CH) in two isostructural sulfonamides leads to drastic differences of activity, phenomenon understood at the atomic level through the high resolution crystallographic structure and kinetic measurements reported in the paper. Combining the tail and the ring approaches in the same chemotype leads to isoform-selective, highly effective sulfonamide CA inhibitors.