tailieunhanh - Báo cáo khoa học: Structural diversity of angiotensin-converting enzyme Insights from structure–activity comparisons of two Drosophila enzymes

The crystal structure of a Drosophila angiotensin-converting enzyme (ANCE) has recently been solved, revealing features important for the binding of ACE inhibitors and allowing molecular comparisons with the structure of human testicular angiotensin-converting enzyme (tACE). ACER is a secondDrosophilaACE that displays both common and dis-tinctive properties. | iFEBS Journal Structural diversity of angiotensin-converting enzyme Insights from structure-activity comparisons of two Drosophila enzymes Richard J. Bingham1 Vincent Dive2 Simon E. V. Phillips1 Alan D. Shirras3 and R. Elwyn Isaac1 1 Astbury Centre for StructuralMolecular Biology Faculty of BiologicalSciences University of Leeds UK 2 Departement d Etudes et d Ingenierie des Proteines Commissariat a l Energie Atomique CE-Saclay Gif-Sur-Yvette France 3 Department of BiologicalSciences University of Lancaster UK Keywords ACE inhibitors angiotensin-converting enzyme ACE Drosophila melanogaster peptide metabolism peptidyl-dipeptidase Correspondence R. E. Isaac Faculty of BiologicalSciences Miall Building University of Leeds Leeds LS2 9JT UK Fax 44 113 34 32835 Tel 44 113 34 32903 E-mail Received 21 September 2005 revised 15 November 2005 accepted 21 November 2005 doi The crystal structure of a Drosophila angiotensin-converting enzyme ANCE has recently been solved revealing features important for the binding of ACE inhibitors and allowing molecular comparisons with the structure of human testicular angiotensin-converting enzyme tACE . ACER is a second Drosophila ACE that displays both common and distinctive properties. Here we report further functional differences between ANCE and ACER and have constructed a homology model of ACER to help explain these. The model predicts a lack of the CE-binding sites and therefore the strong activation of ACER activity towards enkephalinamide peptides by NaCl suggests alternative sites for Cl- binding. There is a marked difference in the electrostatic charge of the substrate channel between ANCE and ACER which may explain why the electropositive peptide MKRSRGPSPRR is cleaved efficiently by ANCE with a low Km but does not bind to ACER. Bradykinin BK peptides are excellent ANCE substrates. Models of BK docked in the substrate channel suggest that the peptide adopts an N-terminal .