PDBsum entry 1v8b

Hydrolase

PDB id: 1v8b

Contents

Protein chains

476 a.a. *

Ligands

NAD ×4

ADN ×4

Waters ×375

* Residue conservation analysis

PDB id:

1v8b

Name:

Hydrolase

Title:

Crystal structure of a hydrolase

Structure:

Adenosylhomocysteinase. Chain: a, b, c, d. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Tetramer (from PQS)

Resolution:

2.40Å R-factor: 0.214 R-free: 0.240

Authors:

N.Tanaka,M.Nakanishi,Y.Kusakabe,K.Shiraiwa,Y.Kitade,K.T.Nakamura

Key ref:

N.Tanaka et al. (2004). Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum. J Mol Biol, 343, 1007-1017. PubMed id: 15476817 DOI: 10.1016/j.jmb.2004.08.104

Date:

03-Jan-04 Release date: 26-Oct-04

Protein chains

P50250  (SAHH_PLAF7) -  Adenosylhomocysteinase from Plasmodium falciparum (isolate 3D7)

Seq: 479 a.a.

Struc: 476 a.a.

Enzyme reactions

• Enzyme class: E.C.3.13.2.1 - adenosylhomocysteinase.
• Reaction: S-adenosyl-L-homocysteine + H2O = L-homocysteine + adenosine

S-adenosyl-L-homocysteine + H2O = L-homocysteine + adenosine (Bound ligand (Het Group name = ADN) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.jmb.2004.08.104

J Mol Biol 343:1007-1017 (2004)

PubMed id: 15476817

Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum.

N.Tanaka, M.Nakanishi, Y.Kusakabe, K.Shiraiwa, S.Yabe, Y.Ito, Y.Kitade, K.T.Nakamura.

ABSTRACT

The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of malarial parasite resistant to conventional drug therapy has stimulated searches for antimalarials with novel modes of action. S-Adenosyl-L-homocysteine hydrolase (SAHH) is a regulator of biological methylations. Inhibitors of SAHH affect the methylation status of nucleic acids, proteins, and small molecules. P.falciparum SAHH (PfSAHH) inhibitors are expected to provide a new type of chemotherapeutic agent against malaria. Despite the pressing need to develop selective PfSAHH inhibitors as therapeutic drugs, only the mammalian SAHH structures are currently available. Here, we report the crystal structure of PfSAHH complexed with the reaction product adenosine (Ado). Knowledge of the structure of the Ado complex in combination with a structural comparison with Homo sapiens SAHH (HsSAHH) revealed that a single substitution between the PfSAHH (Cys59) and HsSAHH (Thr60) accounts for the differential interactions with nucleoside inhibitors. To examine roles of the Cys59 in the interactions with nucleoside inhibitors, a mutant PfSAHH was prepared. A replacement of Cys59 by Thr results in mutant PfSAHH, which shows HsSAHH-like nucleoside inhibitor sensitivity. The present structure should provide opportunities to design potent and selective PfSAHH inhibitors.

Selected figure(s)

Figure 7.
Figure 7. Summary of the inhibitory activities of 2-functional-group-introduced noraristeromycin against HsSAHH, PfSAHH, and mutant PfSAHH (Cys59Thr).

Figure 8.
Figure 8. Surface representation of the active site of PfSAHH. A molecule of 2-F-noraristeromycin (2-F-NAM) is modeled into the Ado-binding site of PfSAHH. Superposition was done with respect to the adenine rings of Ado and 2-F-NAM. The carbon atoms and a fluorine atom are shown in pink and green, respectively. A surface depression that exists specifically in PfSAHH, but not in HsSAHH, is indicated by stars.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 343, 1007-1017) copyright 2004.

Figures were selected by the author.