Interaction of albumin with angiotensin-I-converting enzyme according to molecular modeling data

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Human serum albumin (HSA) is an endogenous inhibitor of angiotensin-I-converting enzyme (ACE), an integral membrane protein that catalyzes the cleavage of angiotensin I decapeptide to angiotensin II octapeptide. By inhibiting ACE, HSA plays a key role in the renin-angiotensin-aldosterone system (RAAS). However, little is known about the mechanism of interaction between these proteins; the structure of the HSA–ACE complex has not yet been obtained experimentally. The purpose of the present work is to investigate the interaction of HSA with ACE in silico. Ten possible HSA–ACE complexes were obtained by the procedure of macromolecular docking. Based on the number of steric and polar contacts between the proteins, the leading complex was selected, the stability of which was then tested by molecular dynamics (MD) simulation. An analysis of the possible effect of modifications in the albumin molecule on its interaction with ACE was performed. A comparative analysis of the structure of the HSA–ACE complex obtained by us, was performed with the known crystal structure of the HSA complex with neonatal Fc receptor (FcRn). The molecular modeling data outline the direction for further study of the mechanisms of HSA–ACE interaction in vitro. Information about these mechanisms will help in the design and improvement of pharmacotherapy aimed at modulating the physiological activity of ACE.

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D. Belinskaia

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: ngoncharov@gmail.com
俄罗斯联邦, St. Petersburg

N. Goncharov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

编辑信件的主要联系方式.
Email: ngoncharov@gmail.com
俄罗斯联邦, St. Petersburg

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2. Fig. 1. Structural organization of human serum albumin (HSA). The DI, DII, and DIII domains of HSA are represented by the orange, purple, and yellow ribbons, respectively. The spheres represent the key amino acids of HSA: the redox site Cys34, the major glycation site Lys525, as well as Tyr150 of the Sudlow I site and Tyr411 of the Sudlow II site, which play a key role in the binding and (pseudo)esterase activities of albumin.

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3. Fig. 2. Structural organization of angiotensin I-converting enzyme (ACE). The ACE molecule is represented by a gray ribbon. The glycosylation sites of ACE are shown as green sticks. The symbol * marks asparagine residues that can potentially be glycosylated in native human ACE but are not glycosylated in recombinant ACE (PDB code 7Q3Y [16]). The active sites of ACE (His361, Glu362, His365, Glu389 in the N-domain and His959, Glu960, His963, Glu987 in the C-domain) are shown as spheres.

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4. Fig. 3. The most probable conformation of the HSA–ACE complex based on macromolecular docking data. The DI, DII, and DIII domains of HSA are shown as orange, purple, and yellow ribbons, respectively. The ACE molecule is shown as a gray ribbon. The glycosylation sites of ACE are shown as green sticks. The * symbol marks asparagine residues that can potentially be glycosylated in native human ACE but are not glycosylated in recombinant ACE (PDB code 7Q3Y [16]). The key amino acids of HSA and the active sites of ACE (His361, Glu362, His365, Glu389 in the N-domain and His959, Glu960, His963, Glu987 in the C-domain) are shown as spheres.

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5. Fig. 4. Specific interactions in the HSA–ACE complex that can be potentially affected by mutations in the albumin molecule: Asp13Asn (a), Glu505Lys (b), and Glu565Lys (c). The DI and DIII domains of HSA are represented by the orange and yellow ribbons, respectively. The ACE molecule is represented by the gray ribbon.

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6. Fig. 5. Topology of the sites of interaction of HSA with macromolecules. The albumin surface is shown in gray, the surfaces of the sites are shown as colored spheres. a – The site of interaction (purple) of native HSA with ACE according to MD data; b – The site of interaction (orange) of native HSA with the FcRn receptor according to X-ray diffraction data [43].

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