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A new high-resolution crystal structure of the Drosophila melanogaster angiotensin converting enzyme homologue, AnCE.

Harrison C, Acharya KR - FEBS Open Bio (2015)

Bottom Line: The presence of ligands originating from the crystallisation condition at the AnCE active site has proved an obstacle to studying the binding of new inhibitor precursors.Here we present the crystal structure of AnCE (in a new crystal form) at 1.85 Å resolution, using crystals grown under different conditions.This new structure may be more suitable for studying the binding of new compounds, with the potential of developing a new generation of improved ACE inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.

ABSTRACT
Angiotensin converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase with an essential role in blood pressure homeostasis in mammals. ACE has long been targeted in the treatment of hypertension through ACE inhibitors, however current inhibitors are known to cause severe side effects. Therefore, there is a requirement for a new generation of ACE inhibitors and structural information will be invaluable in their development. ACE is a challenging enzyme to work with due to its extensive glycosylation. As such, the Drosophila melanogaster ACE homologue, AnCE, which shares ∼60% sequence similarity with human ACE, can be used as a model for studying inhibitor binding. The presence of ligands originating from the crystallisation condition at the AnCE active site has proved an obstacle to studying the binding of new inhibitor precursors. Here we present the crystal structure of AnCE (in a new crystal form) at 1.85 Å resolution, using crystals grown under different conditions. This new structure may be more suitable for studying the binding of new compounds, with the potential of developing a new generation of improved ACE inhibitors.

No MeSH data available.


Related in: MedlinePlus

Interactions between the symmetry molecules at interface 2 in the form II structure results in movement of α2 by 1.3 Å. (a) A surface representation of the interface with one molecule shown in cyan and the symmetry molecule in grey and (b) close-up view of the interface. Interacting residues from the symmetry molecule are shown in grey and those from the central molecule in cyan. Corresponding residues from the new structure are superposed and shown in magenta to illustrate the movement of the peptide backbone in this region. Hydrogen bonding interactions with Asn601, Asp245 and Lys241 of the symmetry molecule in the form II structure pull part of α2 and the loop between α2 and α3 towards the symmetry molecule, resulting in movement of the peptide backbone by up to 1.3 Å compared to in the new structure.
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f0020: Interactions between the symmetry molecules at interface 2 in the form II structure results in movement of α2 by 1.3 Å. (a) A surface representation of the interface with one molecule shown in cyan and the symmetry molecule in grey and (b) close-up view of the interface. Interacting residues from the symmetry molecule are shown in grey and those from the central molecule in cyan. Corresponding residues from the new structure are superposed and shown in magenta to illustrate the movement of the peptide backbone in this region. Hydrogen bonding interactions with Asn601, Asp245 and Lys241 of the symmetry molecule in the form II structure pull part of α2 and the loop between α2 and α3 towards the symmetry molecule, resulting in movement of the peptide backbone by up to 1.3 Å compared to in the new structure.

Mentions: There are further differences between the new structure and the form II structure associated with this interface. As illustrated in Fig. 4, the top of helix α2 and the loop region between α2 and α3 is shifted by up to 1.3 Å towards the symmetry molecule in the form II structure. This is driven by hydrogen bonding between the main chains of Tyr88 and Gln89 with the side chain of Asn601 of the symmetry molecule, and with the side chains of Gln84 and Arg86 with the side chains of Lys241 and Asp245, respectively of the symmetry related molecule.


A new high-resolution crystal structure of the Drosophila melanogaster angiotensin converting enzyme homologue, AnCE.

Harrison C, Acharya KR - FEBS Open Bio (2015)

Interactions between the symmetry molecules at interface 2 in the form II structure results in movement of α2 by 1.3 Å. (a) A surface representation of the interface with one molecule shown in cyan and the symmetry molecule in grey and (b) close-up view of the interface. Interacting residues from the symmetry molecule are shown in grey and those from the central molecule in cyan. Corresponding residues from the new structure are superposed and shown in magenta to illustrate the movement of the peptide backbone in this region. Hydrogen bonding interactions with Asn601, Asp245 and Lys241 of the symmetry molecule in the form II structure pull part of α2 and the loop between α2 and α3 towards the symmetry molecule, resulting in movement of the peptide backbone by up to 1.3 Å compared to in the new structure.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556727&req=5

f0020: Interactions between the symmetry molecules at interface 2 in the form II structure results in movement of α2 by 1.3 Å. (a) A surface representation of the interface with one molecule shown in cyan and the symmetry molecule in grey and (b) close-up view of the interface. Interacting residues from the symmetry molecule are shown in grey and those from the central molecule in cyan. Corresponding residues from the new structure are superposed and shown in magenta to illustrate the movement of the peptide backbone in this region. Hydrogen bonding interactions with Asn601, Asp245 and Lys241 of the symmetry molecule in the form II structure pull part of α2 and the loop between α2 and α3 towards the symmetry molecule, resulting in movement of the peptide backbone by up to 1.3 Å compared to in the new structure.
Mentions: There are further differences between the new structure and the form II structure associated with this interface. As illustrated in Fig. 4, the top of helix α2 and the loop region between α2 and α3 is shifted by up to 1.3 Å towards the symmetry molecule in the form II structure. This is driven by hydrogen bonding between the main chains of Tyr88 and Gln89 with the side chain of Asn601 of the symmetry molecule, and with the side chains of Gln84 and Arg86 with the side chains of Lys241 and Asp245, respectively of the symmetry related molecule.

Bottom Line: The presence of ligands originating from the crystallisation condition at the AnCE active site has proved an obstacle to studying the binding of new inhibitor precursors.Here we present the crystal structure of AnCE (in a new crystal form) at 1.85 Å resolution, using crystals grown under different conditions.This new structure may be more suitable for studying the binding of new compounds, with the potential of developing a new generation of improved ACE inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.

ABSTRACT
Angiotensin converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase with an essential role in blood pressure homeostasis in mammals. ACE has long been targeted in the treatment of hypertension through ACE inhibitors, however current inhibitors are known to cause severe side effects. Therefore, there is a requirement for a new generation of ACE inhibitors and structural information will be invaluable in their development. ACE is a challenging enzyme to work with due to its extensive glycosylation. As such, the Drosophila melanogaster ACE homologue, AnCE, which shares ∼60% sequence similarity with human ACE, can be used as a model for studying inhibitor binding. The presence of ligands originating from the crystallisation condition at the AnCE active site has proved an obstacle to studying the binding of new inhibitor precursors. Here we present the crystal structure of AnCE (in a new crystal form) at 1.85 Å resolution, using crystals grown under different conditions. This new structure may be more suitable for studying the binding of new compounds, with the potential of developing a new generation of improved ACE inhibitors.

No MeSH data available.


Related in: MedlinePlus