PDBsum entry 6t5c

Lyase

PDB id: 6t5c

Contents

Protein chain

258 a.a.

Ligands

BCN

DMS

PEG ×2

MJT

Metals

_ZN

Waters ×391

PDB id:

6t5c

Name:

Lyase

Title:

Human carbonic anhydrase ii bound by anthracene-9-sulfonamide

Structure:

Carbonic anhydrase 2. Chain: a. Fragment: human carbonic anhydrase ii. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.22Å R-factor: 0.126 R-free: 0.153

Authors:

A.Smirnov,E.Manakova,S.Grazulis

Key ref:

V.Dudutienė et al. (2020). Isoform-Selective Enzyme Inhibitors by Exploring Pocket Size According to the Lock-and-Key Principle. Biophys J, 119, 1513-1524. PubMed id: 32971003 DOI: 10.1016/j.bpj.2020.08.037

Date:

15-Oct-19 Release date: 14-Oct-20

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 a.a.

Struc: 258 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.bpj.2020.08.037

Biophys J 119:1513-1524 (2020)

PubMed id: 32971003

Isoform-Selective Enzyme Inhibitors by Exploring Pocket Size According to the Lock-and-Key Principle.

V.Dudutienė, A.Zubrienė, V.Kairys, A.Smirnov, J.Smirnovienė, J.Leitans, A.Kazaks, K.Tars, L.Manakova, S.Gražulis, D.Matulis.

ABSTRACT

In the design of high-affinity and enzyme isoform-selective inhibitors, we applied an approach of augmenting the substituents attached to the benzenesulfonamide scaffold in three ways, namely, substitutions at the 3,5- or 2,4,6-positions or expansion of the condensed ring system. The increased size of the substituents determined the spatial limitations of the active sites of the 12 catalytically active human carbonic anhydrase (CA) isoforms until no binding was observed because of the inability of the compounds to fit in the active site. This approach led to the discovery of high-affinity and high-selectivity compounds for the anticancer target CA IX and antiobesity target CA VB. The x-ray crystallographic structures of compounds bound to CA IX showed the positions of the bound compounds, whereas computational modeling confirmed that steric clashes prevent the binding of these compounds to other isoforms and thus avoid undesired side effects. Such an approach, based on the Lock-and-Key principle, could be used for the development of enzyme-specific drug candidate compounds.