Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

Haitao Zhang, Hamiyet Unal, Cornelius Gati, Gye Won Han, Wei Liu, Nadia 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. TirupulaRussell Desnoyer, Jesse Coe, Chelsie E. Conrad, Petra Fromme, Raymond C. Stevens, Vsevolod Katritch, Sadashiva S. Karnik, Vadim Cherezov

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Angiotensin II type 1 receptor (AT<inf>1</inf>R) 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 AT<inf>1</inf>R blockers (ARBs), the structural basis for AT<inf>1</inf>R 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 AT<inf>1</inf>R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT<inf>1</inf>R-ZD7155 complex structure revealed key structural features of AT<inf>1</inf>R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT<inf>1</inf>R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT<inf>1</inf>R structure-function relationship and structure-based drug design. Structure determination of human Angiotensin II type 1 receptor bound to an antagonist using serial femtosecond crystallography with X-ray free-electron laser and docking studies of other common anti-hypertensive drugs into the structure offer insights into design of blood pressure modulators.

Original languageEnglish (US)
JournalCell
DOIs
StateAccepted/In press - Nov 6 2014

Fingerprint

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

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., ... Cherezov, V. (Accepted/In press). Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography. Cell. 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; 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, 06.11.2014.

Research output: Contribution to journalArticle

Zhang, H, Unal, H, Gati, C, Han, GW, Liu, W, Zatsepin, N, 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 2014, 'Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography', Cell. https://doi.org/10.1016/j.cell.2015.04.011
Zhang, Haitao ; Unal, Hamiyet ; Gati, Cornelius ; Han, Gye Won ; Liu, Wei ; Zatsepin, Nadia ; 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. 2014.
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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-{\AA} 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. Structure determination of human Angiotensin II type 1 receptor bound to an antagonist using serial femtosecond crystallography with X-ray free-electron laser and docking studies of other common anti-hypertensive drugs into the structure offer insights into design of blood pressure modulators.",
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AU - Sawaya, Michael R.

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AU - Messerschmidt, Marc

AU - Williams, Garth J.

AU - Boutet, Sébastien

AU - Yefanov, Oleksandr M.

AU - White, Thomas A.

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AU - Tirupula, Kalyan C.

AU - Desnoyer, Russell

AU - Coe, Jesse

AU - Conrad, Chelsie E.

AU - Fromme, Petra

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