PDBsum entry 5th4

Lyase/lyase inhibitor

PDB id: 5th4

Contents

Protein chain

257 a.a.

Ligands

BEW

GOL

DMS

Metals

_ZN

Waters ×192

PDB id:

5th4

Name:

Lyase/lyase inhibitor

Title:

Crystal structure of 1-hydroxypyridine-2(1h)-thione bound to human carbonic anhydrase 2 l198g

Structure:

Carbonic anhydrase 2. Chain: a. Synonym: carbonate dehydratase ii,carbonic anhydrasE C,cac,carbonic anhydrase ii,ca-ii. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.47Å R-factor: 0.182 R-free: 0.212

Authors:

B.Dick,S.Cohen

Key ref:

B.L.Dick et al. (2017). Effect of donor atom identity on metal-binding pharmacophore coordination. J Biol Inorg Chem, 22, 605-613. PubMed id: 28389830

Date:

29-Sep-16 Release date: 26-Apr-17

Protein chain

P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2 from Homo sapiens

Seq: 260 a.a.

Struc: 257 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

J Biol Inorg Chem 22:605-613 (2017)

PubMed id: 28389830

Effect of donor atom identity on metal-binding pharmacophore coordination.

B.L.Dick, A.Patel, J.A.McCammon, S.M.Cohen.

ABSTRACT

The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms influences the response of the ligand to changes in the protein active site environment. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.