PDBsum entry 6bcc

Lyase/lyase inhibitor

PDB id: 6bcc

Contents

Protein chain

257 a.a.

Ligands

EZL

DOD ×82

Metals

_ZN

PDB id:

6bcc

Name:

Lyase/lyase inhibitor

Title:

Joint x-ray/neutron structure of human carbonic anhydrase ii in complex with ethoxzolamide

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:

1.80Å R-factor: 0.168 R-free: 0.176

Authors:

A.Kovalevsky,R.Mckenna,M.Aggarwal

Key ref:

A.Kovalevsky et al. (2018). "To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation. Structure, 26, 383. PubMed id: 29429876 DOI: 10.1016/j.str.2018.01.006

Date:

20-Oct-17 Release date: 28-Feb-18

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

DOI no: 10.1016/j.str.2018.01.006

Structure 26:383 (2018)

PubMed id: 29429876

"To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation.

A.Kovalevsky, M.Aggarwal, H.Velazquez, M.J.Cuneo, M.P.Blakeley, K.L.Weiss, J.C.Smith, S.Z.Fisher, R.McKenna.

ABSTRACT

Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.