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. Tirupula; Russell Desnoyer; Jesse Coe; Chelsie E. Conrad; Petra Fromme; Raymond C. Stevens; Vsevolod Katritch; Sadashiva S. Karnik; Vadim Cherezov

doi:10.1016/j.cell.2015.04.011

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 journal › Article › peer-review

296 Scopus citations

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 language	English (US)
Pages (from-to)	833-844
Number of pages	12
Journal	Cell
Volume	161
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2015.04.011
State	Published - May 7 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2015.04.011

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Zhang, H., Unal, H., Gati, C., Han, G. W., Liu, W., Zatsepin, N., James, D., Wang, D., Nelson, G., Weierstall, U., Sawaya, M. R., Xu, Q., Messerschmidt, M., Williams, G. J., Boutet, S., Yefanov, O. M., White, T. A., Wang, C., Ishchenko, 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

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 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

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title = "Structure of the angiotensin receptor revealed by serial femtosecond crystallography",

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.",

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

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AU - Zhang, Haitao

AU - Unal, Hamiyet

AU - Gati, Cornelius

AU - Han, Gye Won

AU - Liu, Wei

AU - Zatsepin, Nadia

AU - James, Daniel

AU - Wang, Dingjie

AU - Nelson, Garrett

AU - Weierstall, Uwe

AU - Sawaya, Michael R.

AU - Xu, Qingping

AU - Messerschmidt, Marc

AU - Williams, Garth J.

AU - Boutet, Sébastien

AU - Yefanov, Oleksandr M.

AU - White, Thomas A.

AU - Wang, Chong

AU - Ishchenko, Andrii

AU - Tirupula, Kalyan C.

AU - Desnoyer, Russell

AU - Coe, Jesse

AU - Conrad, Chelsie E.

AU - Fromme, Petra

AU - Stevens, Raymond C.

AU - Katritch, Vsevolod

AU - Karnik, Sadashiva S.

AU - Cherezov, Vadim

PY - 2015/5/7

Y1 - 2015/5/7

N2 - 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.

AB - 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.

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Structure of the angiotensin receptor revealed by serial femtosecond crystallography

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XFEL structure of human Angiotensin Receptor

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Structure of the angiotensin receptor revealed by serial femtosecond crystallography

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XFEL structure of human Angiotensin Receptor

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