PDBsum entry 6bbs

Lyase/lyase inhibitor

PDB id: 6bbs

Contents

Protein chain

257 a.a.

Ligands

BZ1

DOD ×84

Metals

_ZN

PDB id:

6bbs

Name:

Lyase/lyase inhibitor

Title:

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

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:

2.00Å R-factor: 0.276 R-free: 0.287

Authors:

A.Kovalevsky,M.Aggarwal,R.Mckenna

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:

19-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 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.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.