PDBsum entry 4zx5

Hydrolase/hydrolase inhibitor

PDB id: 4zx5

Contents

Protein chain

889 a.a.

Ligands

4TM

DMS ×2

GOL

Metals

_ZN

_MG ×2

Waters ×980

PDB id:

4zx5

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of pfa-m1 in complex with hydroxamic acid- based inhibitor 10q

Structure:

M1 family aminopeptidase. Chain: a. Fragment: unp residues 195-1084. Synonym: pfa-m1. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.95Å R-factor: 0.167 R-free: 0.207

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:

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

Protein chain

O96935  (AMP1_PLAFQ) -  Aminopeptidase N from Plasmodium falciparum (isolate 3D7)

Seq: 1085 a.a.

Struc: 889 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.11.- - ?????

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.