PDBsum entry 6ea2

Hydrolase/hydrolase inhibitor

PDB id: 6ea2

Contents

Protein chain

889 a.a.

Ligands

J1G

DMS ×2

GOL ×3

Metals

_MG ×4

_ZN

Waters ×1377

PDB id:

6ea2

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of pf-m1 in complex with inhibitor (6h) and catalytic zinc ion

Structure:

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

Source:

Plasmodium falciparum (isolate fcb1 / columbia). Organism_taxid: 186763. Strain: isolate fcb1 / columbia. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.35Å R-factor: 0.167 R-free: 0.186

Authors:

N.Drinkwater,S.Mcgowan

Key ref:

N.B.Vinh et al. (2019). Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases. J Med Chem, 62, 622-640. PubMed id: 30537832 DOI: 10.1021/acs.jmedchem.8b01310

Date:

02-Aug-18 Release date: 26-Dec-18

Protein chain

O96935  (AMPN_PLAF7) -  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: 10.1021/acs.jmedchem.8b01310

J Med Chem 62:622-640 (2019)

PubMed id: 30537832

Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.

N.B.Vinh, N.Drinkwater, T.R.Malcolm, M.Kassiou, L.Lucantoni, P.M.Grin, G.S.Butler, S.Duffy, C.M.Overall, V.M.Avery, P.J.Scammells, S.McGowan.

ABSTRACT

There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.