PDBsum entry 2anl

Hydrolase/hydrolase inhibitor

PDB id: 2anl

Contents

Protein chains

327 a.a. *

Ligands

JE2 ×2

Waters ×14

* Residue conservation analysis

PDB id:

2anl

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of the aspartic protease plasmepsin 4 from the malarial parasite plasmodium malariae bound to an allophenylnorstatine based inhibitor

Structure:

Plasmepsin iv. Chain: a, b. Engineered: yes

Source:

Plasmodium malariae. Organism_taxid: 5858. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.30Å R-factor: 0.247 R-free: 0.298

Authors:

J.C.Clemente,L.Govindasamy,A.Madabushi,S.Z.Fisher,R.E.Moose, C.A.Yowell,K.Hidaka,T.Kimura,Y.Hayashi,Y.Kiso,M.Agbandje-Mckenna, J.B.Dame,B.M.Dunn,R.Mckenna

Key ref:

J.C.Clemente et al. (2006). Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor. Acta Crystallogr D Biol Crystallogr, 62, 246-252. PubMed id: 16510971 DOI: 10.1107/S0907444905041260

Date:

11-Aug-05 Release date: 04-Apr-06

Protein chains

O60990  (O60990_PLAMA) -  Plasmepsin from Plasmodium malariae

Seq: 451 a.a.

Struc: 327 a.a.

DOI no: 10.1107/S0907444905041260

Acta Crystallogr D Biol Crystallogr 62:246-252 (2006)

PubMed id: 16510971

Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor.

J.C.Clemente, L.Govindasamy, A.Madabushi, S.Z.Fisher, R.E.Moose, C.A.Yowell, K.Hidaka, T.Kimura, Y.Hayashi, Y.Kiso, M.Agbandje-McKenna, J.B.Dame, B.M.Dunn, R.McKenna.

ABSTRACT

The malarial parasite continues to be one of the leading causes of death in many developing countries. With the development of resistance to the currently available treatments, the discovery of new therapeutics is imperative. Currently, the plasmepsin enzymes found in the food vacuole of the parasite are a chief target for drug development. Allophenylnorstatine-based compounds originally designed to inhibit HIV-1 protease have shown efficacy against all four plasmepsin enzymes found in the food vacuole of Plasmodium falciparum. In this study, the first crystal structure of P. malariae plasmepsin 4 (PmPM4) bound to the allophenylnorstatine-based compound KNI-764 is described at 3.3 A resolution. The PmPM4-inhibitor complex crystallized in the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 95.9, b = 112.6, c = 90.4 A, with two molecules in the asymmetric unit related by a non-crystallographic symmetry operator. The structure was refined to a final R factor of 24.7%. The complex showed the inhibitor in an unexpected binding orientation with allophenylnorstatine occupying the S1' pocket. The P2 group was found outside the S2 pocket, wedged between the flap and a juxtaposed loop. Inhibition analysis of PmPM4 also suggests the potential for allophenylnorstatine-based compounds to be effective against all species of malaria infecting humans and for the future development of a broad-based inhibitor.

Selected figure(s)

Figure 3.
Figure 3 (a) Ribbon diagram of the PmPM4-KNI-764 complex. The PmPM4 -strands, coil and helices are colored yellow, green and red, respectively. KNI-764 is depicted in green sticks. (b) Structural superposition of the C^ trace of PmPM4-KNI-764 (blue), PvPM4-pepstatin A (red; Bernstein et al., 2003[Bernstein, N. K., Cherney, M. M., Yowell, C. A., Dame, J. B. & James, M. N. (2003). J. Mol. Biol. 329, 505-524.]), PfPM4-pepstatin A (green; Asojo et al., 2003[Asojo, O. A., Gulnik, S. V., Afonina, E., Yu, B., Ellman, J. A., Haque, T. S. & Silva, A. M. (2003). J. Mol. Biol. 327, 173-181.]) and PfPM2-Eh58 (orange; Asojo et al., 2003[Asojo, O. A., Gulnik, S. V., Afonina, E., Yu, B., Ellman, J. A., Haque, T. S. & Silva, A. M. (2003). J. Mol. Biol. 327, 173-181.]). This figure was generated using PyMOL (DeLano, 2002[DeLano, W. L. (2002). The PyMOL Molecular Graphics System. http://www.pymol.org .]).

Figure 5.
Figure 5 Stereoviews of KNI-764 in the active site of PmPM4. (a) View of P1 and P2 of KNI-764. (b) View of P1' and P2' of KNI-764. The surface of the active site is shown as a beige Connolly surface. PmPm4 is shown as a red ribbon. KNI-764 is modeled as blue sticks. The residues of the flaps (Ile75-Val82) and the 290s loop (Leu290-Glu295) are depicted as green sticks. (c) Plausible hydrogen-bonding interactions (red broken lines) between PmPM4 and KNI-764.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2006, 62, 246-252) copyright 2006.

Figures were selected by the author.