PDBsum entry 4r6t

Hydrolase/hydrolase inhibitor

PDB id: 4r6t

Contents

Protein chains

(+ 6 more) 514 a.a.

Ligands

CO3 ×12

SO4 ×23

R5T ×12

1PE ×20

DMS

Metals

_ZN ×24

Waters ×1691

PDB id:

4r6t

Name:

Hydrolase/hydrolase inhibitor

Title:

Structure of the m17 leucyl aminopeptidase from malaria complexed with a hydroxamic acid-based inhibitor

Structure:

M17 leucyl aminopeptidase. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Engineered: yes

Source:

Plasmodium falciparum 3d7. Organism_taxid: 36329. Gene: lap, pf14_0439. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.60Å R-factor: 0.214 R-free: 0.269

Authors:

N.Drinkwater,S.Mcgowan

Key ref:

S.N.Mistry et al. (2014). Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. J Med Chem, 57, 9168-9183. PubMed id: 25299353 DOI: 10.1021/jm501323a

Date:

26-Aug-14 Release date: 29-Oct-14

Protein chains

Q8IL11  (Q8IL11_PLAF7) -  Leucine aminopeptidase from Plasmodium falciparum (isolate 3D7)

Seq: 605 a.a.

Struc: 514 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.3.4.13.- - ?????

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: 10.1021/jm501323a

J Med Chem 57:9168-9183 (2014)

PubMed id: 25299353

Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors.

S.N.Mistry, N.Drinkwater, C.Ruggeri, K.K.Sivaraman, S.Loganathan, S.Fletcher, M.Drag, A.Paiardini, V.M.Avery, P.J.Scammells, S.McGowan.

ABSTRACT

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.