PDBsum entry 4zwx

Lyase/lyase inhibitor

PDB id: 4zwx

Contents

Protein chain

257 a.a.

Ligands

DMS ×2

5KZ

Metals

_ZN

Waters ×198

PDB id:

4zwx

Name:

Lyase/lyase inhibitor

Title:

Engineered carbonic anhydrase ix mimic in complex with glucosyl sulfamate inhibitor

Structure:

Carbonic anhydrase 2. Chain: a. Fragment: unp residues 4-260. 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:

1.70Å R-factor: 0.176 R-free: 0.212

Authors:

B.P.Mahon,C.L.Lomelino,A.L.Salguero,R.Mckenna

Key ref:

B.P.Mahon et al. (2015). Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of Glucosyl-Based Sulfamates. J Med Chem, 58, 6630-6638. PubMed id: 26203869 DOI: 10.1021/acs.jmedchem.5b00845

Date:

19-May-15 Release date: 28-Oct-15

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 7 residue positions (black crosses)

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: 10.1021/acs.jmedchem.5b00845

J Med Chem 58:6630-6638 (2015)

PubMed id: 26203869

Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of Glucosyl-Based Sulfamates.

B.P.Mahon, C.L.Lomelino, J.Ladwig, G.M.Rankin, J.M.Driscoll, A.L.Salguero, M.A.Pinard, D.Vullo, C.T.Supuran, S.A.Poulsen, R.McKenna.

ABSTRACT

Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 Å or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically "map" key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.