Crystal structure of a phosphonotripeptide K-26 in complex with angiotensin converting enzyme homologue (AnCE) from Drosophila melanogaster

Mohd Akif; Ioanna Ntai; Edward D. Sturrock; R. Elwyn Isaac; Brian O. Bachmann; K. Ravi Acharya

doi:10.1016/j.bbrc.2010.06.113

Crystal structure of a phosphonotripeptide K-26 in complex with angiotensin converting enzyme homologue (AnCE) from Drosophila melanogaster

Mohd Akif, Ioanna Ntai, Edward D. Sturrock, R. Elwyn Isaac, Brian O. Bachmann, K. Ravi Acharya^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Angiotensin-I converting enzyme (ACE, a zinc dependent dipeptidyl carboxypeptidase) is a major target of drugs due to its role in the modulation of blood pressure and cardiovascular disorders. Here we present a crystal structure of AnCE (an ACE homologue from Drosophila melanogaster with a single enzymatic domain) in complex with a natural product-phosphonotripeptide, K-26 at 1.96Å resolution. The inhibitor binds exclusively in the S₁ and S₂ binding pockets of AnCE (coordinating the zinc ion) through ionic and hydrogen bond interactions. A detailed structural comparison of AnCE·K-26 complex with individual domains of human somatic ACE provides useful information for further exploration of ACE inhibitor pharmacophores involving phosphonic acids.

Original language	English (US)
Pages (from-to)	532-536
Number of pages	5
Journal	Biochemical and Biophysical Research Communications
Volume	398
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2010.06.113
State	Published - Jul 2010

Keywords

Angiotensin converting enzyme
Drosophila melanogaster
Inhibitor binding
X-ray crystallography
Zinc metallopeptidase

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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title = "Crystal structure of a phosphonotripeptide K-26 in complex with angiotensin converting enzyme homologue (AnCE) from Drosophila melanogaster",

abstract = "Angiotensin-I converting enzyme (ACE, a zinc dependent dipeptidyl carboxypeptidase) is a major target of drugs due to its role in the modulation of blood pressure and cardiovascular disorders. Here we present a crystal structure of AnCE (an ACE homologue from Drosophila melanogaster with a single enzymatic domain) in complex with a natural product-phosphonotripeptide, K-26 at 1.96{\AA} resolution. The inhibitor binds exclusively in the S1 and S2 binding pockets of AnCE (coordinating the zinc ion) through ionic and hydrogen bond interactions. A detailed structural comparison of AnCE·K-26 complex with individual domains of human somatic ACE provides useful information for further exploration of ACE inhibitor pharmacophores involving phosphonic acids.",

keywords = "Angiotensin converting enzyme, Drosophila melanogaster, Inhibitor binding, X-ray crystallography, Zinc metallopeptidase",

author = "Mohd Akif and Ioanna Ntai and Sturrock, {Edward D.} and Isaac, {R. Elwyn} and Bachmann, {Brian O.} and Acharya, {K. Ravi}",

note = "Funding Information: This work was supported by the Medical Research Council (UK) through a Project Grant (Number 81272 ) and a Royal Society (UK) Industry Fellowship to K.R.A. We thank the scientists at station IO3 of Diamond Light Source, Didcot, Oxon (UK) and Nethaji Thiyagarajan for their support during X-ray diffraction data collection.",

year = "2010",

month = jul,

doi = "10.1016/j.bbrc.2010.06.113",

language = "English (US)",

volume = "398",

pages = "532--536",

journal = "Biochemical and Biophysical Research Communications",

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T1 - Crystal structure of a phosphonotripeptide K-26 in complex with angiotensin converting enzyme homologue (AnCE) from Drosophila melanogaster

AU - Akif, Mohd

AU - Ntai, Ioanna

AU - Sturrock, Edward D.

AU - Isaac, R. Elwyn

AU - Bachmann, Brian O.

AU - Acharya, K. Ravi

N1 - Funding Information: This work was supported by the Medical Research Council (UK) through a Project Grant (Number 81272 ) and a Royal Society (UK) Industry Fellowship to K.R.A. We thank the scientists at station IO3 of Diamond Light Source, Didcot, Oxon (UK) and Nethaji Thiyagarajan for their support during X-ray diffraction data collection.

PY - 2010/7

Y1 - 2010/7

N2 - Angiotensin-I converting enzyme (ACE, a zinc dependent dipeptidyl carboxypeptidase) is a major target of drugs due to its role in the modulation of blood pressure and cardiovascular disorders. Here we present a crystal structure of AnCE (an ACE homologue from Drosophila melanogaster with a single enzymatic domain) in complex with a natural product-phosphonotripeptide, K-26 at 1.96Å resolution. The inhibitor binds exclusively in the S1 and S2 binding pockets of AnCE (coordinating the zinc ion) through ionic and hydrogen bond interactions. A detailed structural comparison of AnCE·K-26 complex with individual domains of human somatic ACE provides useful information for further exploration of ACE inhibitor pharmacophores involving phosphonic acids.

AB - Angiotensin-I converting enzyme (ACE, a zinc dependent dipeptidyl carboxypeptidase) is a major target of drugs due to its role in the modulation of blood pressure and cardiovascular disorders. Here we present a crystal structure of AnCE (an ACE homologue from Drosophila melanogaster with a single enzymatic domain) in complex with a natural product-phosphonotripeptide, K-26 at 1.96Å resolution. The inhibitor binds exclusively in the S1 and S2 binding pockets of AnCE (coordinating the zinc ion) through ionic and hydrogen bond interactions. A detailed structural comparison of AnCE·K-26 complex with individual domains of human somatic ACE provides useful information for further exploration of ACE inhibitor pharmacophores involving phosphonic acids.

KW - Angiotensin converting enzyme

KW - Drosophila melanogaster

KW - Inhibitor binding

KW - X-ray crystallography

KW - Zinc metallopeptidase

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JO - Biochemical and Biophysical Research Communications

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Crystal structure of a phosphonotripeptide K-26 in complex with angiotensin converting enzyme homologue (AnCE) from Drosophila melanogaster

Abstract

Keywords

ASJC Scopus subject areas

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