Structure of the angiotensin receptor revealed by serial femtosecond crystallography

Haitao Zhang, Hamiyet Unal, Cornelius Gati, Gye Won Han, Wei Liu, Nadia A. Zatsepin, Daniel James, Dingjie Wang, Garrett Nelson, Uwe Weierstall, Michael R. Sawaya, Qingping Xu, Marc Messerschmidt, Garth J. Williams, Sébastien Boutet, Oleksandr M. Yefanov, Thomas A. White, Chong Wang, Andrii Ishchenko, Kalyan C. Tirupula & 8 others Russell Desnoyer, Jesse Coe, Chelsie E. Conrad, Petra Fromme, Raymond C. Stevens, Vsevolod Katritch, Sadashiva S. Karnik, Vadim Cherezov

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.

Original languageEnglish
Pages (from-to)833-844
Number of pages12
JournalCell
Volume161
Issue number4
DOIs
Publication statusPublished - May 7 2015

Fingerprint

Angiotensin Type 1 Receptor
Crystallography
Angiotensin Receptors
Angiotensin II Type 1 Receptor Blockers
Antihypertensive Agents
Synchrotrons
X ray lasers
Drug Design
X Ray Crystallography
G-Protein-Coupled Receptors
Free electron lasers
Blood pressure
Synchrotron radiation
Lasers
Maintenance
Electrons
Radiation
Blood Pressure
Ligands
Crystal structure

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, H., Unal, H., Gati, C., Han, G. W., Liu, W., Zatsepin, N. A., ... Cherezov, V. (2015). Structure of the angiotensin receptor revealed by serial femtosecond crystallography. Cell, 161(4), 833-844. https://doi.org/10.1016/j.cell.2015.04.011

Structure of the angiotensin receptor revealed by serial femtosecond crystallography. / Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; Han, Gye Won; Liu, Wei; Zatsepin, Nadia A.; James, Daniel; Wang, Dingjie; Nelson, Garrett; Weierstall, Uwe; Sawaya, Michael R.; Xu, Qingping; Messerschmidt, Marc; Williams, Garth J.; Boutet, Sébastien; Yefanov, Oleksandr M.; White, Thomas A.; Wang, Chong; Ishchenko, Andrii; Tirupula, Kalyan C.; Desnoyer, Russell; Coe, Jesse; Conrad, Chelsie E.; Fromme, Petra; Stevens, Raymond C.; Katritch, Vsevolod; Karnik, Sadashiva S.; Cherezov, Vadim.

In: Cell, Vol. 161, No. 4, 07.05.2015, p. 833-844.

Research output: Contribution to journalArticle

Zhang, H, Unal, H, Gati, C, Han, GW, Liu, W, Zatsepin, NA, James, D, Wang, D, Nelson, G, Weierstall, U, Sawaya, MR, Xu, Q, Messerschmidt, M, Williams, GJ, Boutet, S, Yefanov, OM, White, TA, Wang, C, Ishchenko, A, Tirupula, KC, Desnoyer, R, Coe, J, Conrad, CE, Fromme, P, Stevens, RC, Katritch, V, Karnik, SS & Cherezov, V 2015, 'Structure of the angiotensin receptor revealed by serial femtosecond crystallography', Cell, vol. 161, no. 4, pp. 833-844. https://doi.org/10.1016/j.cell.2015.04.011
Zhang H, Unal H, Gati C, Han GW, Liu W, Zatsepin NA et al. Structure of the angiotensin receptor revealed by serial femtosecond crystallography. Cell. 2015 May 7;161(4):833-844. https://doi.org/10.1016/j.cell.2015.04.011
Zhang, Haitao ; Unal, Hamiyet ; Gati, Cornelius ; Han, Gye Won ; Liu, Wei ; Zatsepin, Nadia A. ; James, Daniel ; Wang, Dingjie ; Nelson, Garrett ; Weierstall, Uwe ; Sawaya, Michael R. ; Xu, Qingping ; Messerschmidt, Marc ; Williams, Garth J. ; Boutet, Sébastien ; Yefanov, Oleksandr M. ; White, Thomas A. ; Wang, Chong ; Ishchenko, Andrii ; Tirupula, Kalyan C. ; Desnoyer, Russell ; Coe, Jesse ; Conrad, Chelsie E. ; Fromme, Petra ; Stevens, Raymond C. ; Katritch, Vsevolod ; Karnik, Sadashiva S. ; Cherezov, Vadim. / Structure of the angiotensin receptor revealed by serial femtosecond crystallography. In: Cell. 2015 ; Vol. 161, No. 4. pp. 833-844.
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