PDBsum entry 4zy2

Hydrolase/hydrolase inhibitor

PDB id: 4zy2

Contents

Protein chains

(+ 6 more) 519 a.a.

Ligands

CO3 ×12

SO4 ×28

1PE ×39

4TL ×12

DMS ×3

Metals

_ZN ×24

Waters ×4805

PDB id:

4zy2

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of pfa-m17 in complex with hydroxamic acid- based inhibitor 10o

Structure:

Probable m17 family aminopeptidase. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Fragment: unp residues 84-605. Engineered: yes. Mutation: yes

Source:

Plasmodium falciparum fcb1/columbia. Organism_taxid: 186763. Strain: isolate fcb1 / columbia. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.10Å R-factor: 0.196 R-free: 0.239

Authors:

N.Drinkwater,S.Mcgowan

Key ref:

N.Drinkwater et al. (2016). Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. Eur J Med Chem, 110, 43-64. PubMed id: 26807544 DOI: 10.1016/j.ejmech.2016.01.015

Date:

21-May-15 Release date: 30-Mar-16

Protein chains

A0A0L7M119  (A0A0L7M119_PLAF4) -  leucyl aminopeptidase from Plasmodium falciparum (isolate Dd2)

Seq: 606 a.a.

Struc: 519 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: E.C.3.4.11.1 - leucyl aminopeptidase.
• Reaction: Release of an N-terminal amino acid, Xaa-|-Xbb-, in which Xaa is preferably Leu, but may be other amino acids including Pro although not Arg or Lys, and Xbb may be Pro.
• Cofactor: Zn(2+)
• Enzyme class 3: E.C.3.4.11.5 - prolyl aminopeptidase.
• Reaction: Release of a N-terminal proline from a peptide.
• Cofactor: Mn(2+)

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.

DOI no: 10.1016/j.ejmech.2016.01.015

Eur J Med Chem 110:43-64 (2016)

PubMed id: 26807544

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.

N.Drinkwater, N.B.Vinh, S.N.Mistry, R.S.Bamert, C.Ruggeri, J.P.Holleran, S.Loganathan, A.Paiardini, S.A.Charman, A.K.Powell, V.M.Avery, S.McGowan, P.J.Scammells.

ABSTRACT

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.