Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax

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 extensi...

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Main Authors: Alag, Reema, Balakrishna, Asha Manikkoth, Rajan, Sreekanth, Qureshi, Insaf A., Shin, Joon, Lescar, Julien, Grüber, Gerhard, Yoon, Ho Sup
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2015
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Online Access:https://hdl.handle.net/10356/106116
http://hdl.handle.net/10220/26349
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spelling sg-ntu-dr.10356-1061162023-02-28T17:06:22Z Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax Alag, Reema Balakrishna, Asha Manikkoth Rajan, Sreekanth Qureshi, Insaf A. Shin, Joon Lescar, Julien Grüber, Gerhard Yoon, Ho Sup School of Biological Sciences DRNTU::Science::Biological sciences 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. Published version 2015-07-08T04:15:56Z 2019-12-06T22:04:51Z 2015-07-08T04:15:56Z 2019-12-06T22:04:51Z 2013 2013 Journal Article Alag, R., Balakrishna, A. M., Rajan, S., Qureshi, I. A., Shin, J., Lescar, J., et al. (2013). Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax. Eukaryotic cell, 12(4), 627-634. 1535-9778 https://hdl.handle.net/10356/106116 http://hdl.handle.net/10220/26349 10.1128/EC.00016-13 23435727 en Eukaryotic cell © 2013 American Society for Microbiology. This paper was published in Eukaryotic Cell and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology. The published version is available at: [http://dx.doi.org/10.1128/EC.00016-13]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Alag, Reema
Balakrishna, Asha Manikkoth
Rajan, Sreekanth
Qureshi, Insaf A.
Shin, Joon
Lescar, Julien
Grüber, Gerhard
Yoon, Ho Sup
Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Alag, Reema
Balakrishna, Asha Manikkoth
Rajan, Sreekanth
Qureshi, Insaf A.
Shin, Joon
Lescar, Julien
Grüber, Gerhard
Yoon, Ho Sup
format Article
author Alag, Reema
Balakrishna, Asha Manikkoth
Rajan, Sreekanth
Qureshi, Insaf A.
Shin, Joon
Lescar, Julien
Grüber, Gerhard
Yoon, Ho Sup
author_sort Alag, Reema
title Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
title_short Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
title_full Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
title_fullStr Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
title_full_unstemmed Structural insights into substrate binding by PvFKBP35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
title_sort structural insights into substrate binding by pvfkbp35, a peptidylprolyl cis-trans isomerase from the human malarial parasite plasmodium vivax
publishDate 2015
url https://hdl.handle.net/10356/106116
http://hdl.handle.net/10220/26349
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