Structural Insights into Substrate Binding by PvFKBP35, a Peptidylprolyl cis-trans Isomerase from the Human Malarial Parasite Plasmodium vivax

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Published inEukaryotic Cell Vol. 12; no. 4; pp. 627 - 634
Main Authors Alag, Reema, Balakrishna, Asha Manikkoth, Rajan, Sreekanth, Qureshi, Insaf A, Shin, Joon, Lescar, Julien, Grüber, Gerhard, Yoon, Ho Sup
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 01.04.2013
Subjects
Binding Sites
Crystallography, X-Ray
Escherichia coli - genetics
Kinetics
Molecular Docking Simulation
Oligopeptides - chemistry
Oligopeptides - metabolism
Peptidylprolyl Isomerase - chemistry
Peptidylprolyl Isomerase - genetics
Peptidylprolyl Isomerase - metabolism
Plasmodium vivax
Plasmodium vivax - chemistry
Plasmodium vivax - genetics
Plasmodium vivax - metabolism
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Protozoan Proteins - chemistry
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Substrate Specificity
Tacrolimus Binding Proteins - chemistry
Tacrolimus Binding Proteins - genetics
Tacrolimus Binding Proteins - metabolism
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The immunosuppressive drug FK506 binding proteins (FKBPs), an immunophilin family with the immunosuppressive drug FK506 binding property, exhibit peptidylprolyl cis-trans isomerase (PPIase) activity. While the cyclophilin-catalyzed peptidylprolyl isomerization of X-Pro peptide bonds has been extensively studied, the mechanism of the FKBP-mediated peptidylprolyl isomerization remains uncharacterized. Thus, to investigate the binding of FKBP with its substrate and the underlying catalytic mechanism of the FKBP-mediated proline isomerization, here we employed the FK506 binding domain (FKBD) of the human malarial parasite Plasmodium vivax FK506 binding protein 35 ( Pv FKBP35) and examined the details of the molecular interaction between the isomerase and a peptide substrate. The crystallographic structures of apo Pv FKBD35 and its complex with the tetrapeptide substrate succinyl-Ala-Leu-Pro-Phe- p -nitroanilide (sALPFp) determined at 1.4 Å and 1.65 Å resolutions, respectively, showed that the substrate binds to Pv FKBD35 in a cis conformation. Nuclear magnetic resonance (NMR) studies demonstrated the chemical shift perturbations of D55, H67, V73, and I74 residues upon the substrate binding. In addition, the X-ray crystal structure, along with the mutational studies, shows that Y100 is a key residue for the catalytic activity. Taken together, our results provide insights into the catalytic mechanism of Pv FKBP35-mediated cis-trans isomerization of substrate and ultimately might aid designing substrate mimetic inhibitors targeting the malarial parasite FKBPs.
The immunosuppressive drug FK506 binding proteins (FKBPs), an immunophilin family with the immunosuppressive drug FK506 binding property, exhibit peptidylprolyl cis-trans isomerase (PPIase) activity. While the cyclophilin-catalyzed peptidylprolyl isomerization of X-Pro peptide bonds has been extensively studied, the mechanism of the FKBP-mediated peptidylprolyl isomerization remains uncharacterized. Thus, to investigate the binding of FKBP with its substrate and the underlying catalytic mechanism of the FKBP-mediated proline isomerization, here we employed the FK506 binding domain (FKBD) of the human malarial parasite Plasmodium vivax FK506 binding protein 35 (PvFKBP35) and examined the details of the molecular interaction between the isomerase and a peptide substrate. The crystallographic structures of apo PvFKBD35 and its complex with the tetrapeptide substrate succinyl-Ala-Leu-Pro-Phe-p-nitroanilide (sALPFp) determined at 1.4 Aa and 1.65 Aa resolutions, respectively, showed that the substrate binds to PvFKBD35 in a cis conformation. Nuclear magnetic resonance (NMR) studies demonstrated the chemical shift perturbations of D55, H67, V73, and I74 residues upon the substrate binding. In addition, the X-ray crystal structure, along with the mutational studies, shows that Y100 is a key residue for the catalytic activity. Taken together, our results provide insights into the catalytic mechanism of PvFKBP35-mediated cis-trans isomerization of substrate and ultimately might aid designing substrate mimetic inhibitors targeting the malarial parasite FKBPs.
The immunosuppressive drug FK506 binding proteins (FKBPs), an immunophilin family with the immunosuppressive drug FK506 binding property, exhibit peptidylprolyl cis-trans isomerase (PPIase) activity. While the cyclophilin-catalyzed peptidylprolyl isomerization of X-Pro peptide bonds has been extensively studied, the mechanism of the FKBP-mediated peptidylprolyl isomerization remains uncharacterized. Thus, to investigate the binding of FKBP with its substrate and the underlying catalytic mechanism of the FKBP-mediated proline isomerization, here we employed the FK506 binding domain (FKBD) of the human malarial parasite Plasmodium vivax FK506 binding protein 35 (PvFKBP35) and examined the details of the molecular interaction between the isomerase and a peptide substrate. The crystallographic structures of apo PvFKBD35 and its complex with the tetrapeptide substrate succinyl-Ala-Leu-Pro-Phe-p-nitroanilide (sALPFp) determined at 1.4 Å and 1.65 Å resolutions, respectively, showed that the substrate binds to PvFKBD35 in a cis conformation. Nuclear magnetic resonance (NMR) studies demonstrated the chemical shift perturbations of D55, H67, V73, and I74 residues upon the substrate binding. In addition, the X-ray crystal structure, along with the mutational studies, shows that Y100 is a key residue for the catalytic activity. Taken together, our results provide insights into the catalytic mechanism of PvFKBP35-mediated cis-trans isomerization of substrate and ultimately might aid designing substrate mimetic inhibitors targeting the malarial parasite FKBPs.
Author Julien Lescar
Insaf A. Qureshi
Reema Alag
Gerhard Grüber
Sreekanth Rajan
Joon Shin
Asha Manikkoth Balakrishna
Ho Sup Yoon
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R.A., A.M.B., and S.R. contributed equally to this work.
Present address: Insaf A. Qureshi, Department of Biotechnology, School of Life Sciences, University of Hyderabad, Gachi Bowli, Hyderabad, India.
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The immunosuppressive drug FK506 binding proteins (FKBPs), an immunophilin family with the immunosuppressive drug FK506 binding property, exhibit...
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SubjectTerms Binding Sites
Crystallography, X-Ray
Escherichia coli - genetics
Kinetics
Molecular Docking Simulation
Oligopeptides - chemistry
Oligopeptides - metabolism
Peptidylprolyl Isomerase - chemistry
Peptidylprolyl Isomerase - genetics
Peptidylprolyl Isomerase - metabolism
Plasmodium vivax
Plasmodium vivax - chemistry
Plasmodium vivax - genetics
Plasmodium vivax - metabolism
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Protozoan Proteins - chemistry
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Substrate Specificity
Tacrolimus Binding Proteins - chemistry
Tacrolimus Binding Proteins - genetics
Tacrolimus Binding Proteins - metabolism
Title Structural Insights into Substrate Binding by PvFKBP35, a Peptidylprolyl cis-trans Isomerase from the Human Malarial Parasite Plasmodium vivax
URI http://ec.asm.org/content/12/4/627.abstract
https://www.ncbi.nlm.nih.gov/pubmed/23435727
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Volume 12
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