6I3I

Crystal structure of reactive center loop (RCL) cleaved angiotensinogen

Summary for 6I3I

• Entry DOI: 10.2210/pdb6i3i/pdb
• Descriptor: Angiotensinogen, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: angiotensinogen, reactive center loop, hormone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 50868.86

Authors

Yan, Y.,Read, R.J. (deposition date: 2018-11-06, release date: 2018-12-26, Last modification date: 2024-11-06)

Primary citation

Yan, Y.,Zhou, A.,Carrell, R.W.,Read, R.J.
Structural basis for the specificity of renin-mediated angiotensinogen cleavage.
J. Biol. Chem., 294:2353-2364, 2019

PubMed Abstract: The renin-angiotensin cascade is a hormone system that regulates blood pressure and fluid balance. Renin-mediated cleavage of the angiotensin I peptide from the N terminus of angiotensinogen (AGT) is the rate-limiting step of this cascade; however, the detailed molecular mechanism underlying this step is unclear. Here, we solved the crystal structures of glycosylated human AGT (2.30 Å resolution), its encounter complex with renin (2.55 Å), AGT cleaved in its reactive center loop (RCL; 2.97 Å), and spent AGT from which the N-terminal angiotensin peptide was removed (2.63 Å). These structures revealed that AGT undergoes profound conformational changes and binds renin through a tail-into-mouth allosteric mechanism that inserts the N terminus into a pocket equivalent to a hormone-binding site on other serpins. These changes fully extended the N-terminal tail, with the scissile bond for angiotensin release docked in renin's active site. Insertion of the N terminus into this pocket accompanied a complete unwinding of helix H of AGT, which, in turn, formed key interactions with renin in the complementary binding interface. Mutagenesis and kinetic analyses confirmed that renin-mediated production of angiotensin I is controlled by interactions of amino acid residues and glycan components outside renin's active-site cleft. Our findings indicate that AGT adapts unique serpin features for hormone delivery and binds renin through concerted movements in the N-terminal tail and in its main body to modulate angiotensin release. These insights provide a structural basis for the development of agents that attenuate angiotensin release by targeting AGT's hormone binding pocket.

PubMed: 30563843
DOI: 10.1074/jbc.RA118.006608

Experimental method

X-RAY DIFFRACTION (2.97 Å)