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Title: Structural basis for selectivity and diversity in angiotensin II receptors

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFNIH
OSTI Identifier:
1368259
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature (London); Journal Volume: 544; Journal Issue: 7650
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Zhang, Haitao, Han, Gye Won, Batyuk, Alexander, Ishchenko, Andrii, White, Kate L., Patel, Nilkanth, Sadybekov, Anastasiia, Zamlynny, Beata, Rudd, Michael T., Hollenstein, Kaspar, Tolstikova, Alexandra, White, Thomas A., Hunter, Mark S., Weierstall, Uwe, Liu, Wei, Babaoglu, Kerim, Moore, Eric L., Katz, Ryan D., Shipman, Jennifer M., Garcia-Calvo, Margarita, Sharma, Sujata, Sheth, Payal, Soisson, Stephen M., Stevens, Raymond C., Katritch, Vsevolod, and Cherezov, Vadim. Structural basis for selectivity and diversity in angiotensin II receptors. United States: N. p., 2017. Web. doi:10.1038/nature22035.
Zhang, Haitao, Han, Gye Won, Batyuk, Alexander, Ishchenko, Andrii, White, Kate L., Patel, Nilkanth, Sadybekov, Anastasiia, Zamlynny, Beata, Rudd, Michael T., Hollenstein, Kaspar, Tolstikova, Alexandra, White, Thomas A., Hunter, Mark S., Weierstall, Uwe, Liu, Wei, Babaoglu, Kerim, Moore, Eric L., Katz, Ryan D., Shipman, Jennifer M., Garcia-Calvo, Margarita, Sharma, Sujata, Sheth, Payal, Soisson, Stephen M., Stevens, Raymond C., Katritch, Vsevolod, & Cherezov, Vadim. Structural basis for selectivity and diversity in angiotensin II receptors. United States. doi:10.1038/nature22035.
Zhang, Haitao, Han, Gye Won, Batyuk, Alexander, Ishchenko, Andrii, White, Kate L., Patel, Nilkanth, Sadybekov, Anastasiia, Zamlynny, Beata, Rudd, Michael T., Hollenstein, Kaspar, Tolstikova, Alexandra, White, Thomas A., Hunter, Mark S., Weierstall, Uwe, Liu, Wei, Babaoglu, Kerim, Moore, Eric L., Katz, Ryan D., Shipman, Jennifer M., Garcia-Calvo, Margarita, Sharma, Sujata, Sheth, Payal, Soisson, Stephen M., Stevens, Raymond C., Katritch, Vsevolod, and Cherezov, Vadim. Wed . "Structural basis for selectivity and diversity in angiotensin II receptors". United States. doi:10.1038/nature22035.
@article{osti_1368259,
title = {Structural basis for selectivity and diversity in angiotensin II receptors},
author = {Zhang, Haitao and Han, Gye Won and Batyuk, Alexander and Ishchenko, Andrii and White, Kate L. and Patel, Nilkanth and Sadybekov, Anastasiia and Zamlynny, Beata and Rudd, Michael T. and Hollenstein, Kaspar and Tolstikova, Alexandra and White, Thomas A. and Hunter, Mark S. and Weierstall, Uwe and Liu, Wei and Babaoglu, Kerim and Moore, Eric L. and Katz, Ryan D. and Shipman, Jennifer M. and Garcia-Calvo, Margarita and Sharma, Sujata and Sheth, Payal and Soisson, Stephen M. and Stevens, Raymond C. and Katritch, Vsevolod and Cherezov, Vadim},
abstractNote = {},
doi = {10.1038/nature22035},
journal = {Nature (London)},
number = 7650,
volume = 544,
place = {United States},
year = {Wed Apr 05 00:00:00 EDT 2017},
month = {Wed Apr 05 00:00:00 EDT 2017}
}
  • The angiotensin II receptors AT 1R and AT 2R serve as key components of the renin–angiotensin–aldosterone system. AT 1R has a central role in the regulation of blood pressure, but the function of AT 2R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT 2R bound to an AT 2R-selective ligand and to an AT 1R/AT 2R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position,more » stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure–activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Finally, our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.« less
  • Specific, high-affinity (K/sub d/ approx. = 0.6 nM), and saturable (3.3 fmol/mg of tissue, wet weight) binding of /sup 125/I-labeled (Sar/sup 1/,Ile/sup 8/)angiotensin II to rat ovarian membranes was observed. Displacement of /sup 125/I-labeled (Sar/sup 1/,Ile/sup 8/)angiotensin II binding to rat ovarian membranes by angiotensin II analogs and fragments resembled the potency order of these compounds on angiotensin II receptors in other tissues. Several unrelated peptides, including follicle-stimulating hormone at 10..mu..M, did not displace ovarian /sup 125/I-labeled (Sar/sup 1/, Ile/sup 8/)angiotensin II binding. Autoradiograms of /sup 125/I-labeled (Sar/sup 1/,Ile/sup 8/)angiotensin II binding to ovarian sections indicated that the angiotensin IImore » receptor binding sites were localized exclusively to a subpopulation of follicles, occurring on the granulosa and theca interna cells. Other follicles were devoid of /sup 125/I-labeled (Sar/sup 1/,Ile/sup 8/)angiotensin II binding sites. Angiotensin II immunoreactive material was also identified in the ovary. The concentration of ovarian Ang II immunoreactivity was 8- to 75-fold greater than that of plasma, was not reduced in bilaterally nephrectomized rats, and was shown by high-pressure liquid chromatographic analysis to be the native angiotensin II octapeptide. The presence of angiotensin II and its receptor binding sites in the ovary suggests a role for angiotensin II as a regulator of ovarian function.« less
  • Membrane-bound cGMP-dependent protein kinase (PKG) II is an important regulator of bone growth, renin secretion, and memory formation. Despite its crucial physiological roles, little is known about its cyclic nucleotide selectivity mechanism due to a lack of structural information. Here, we find that the C-terminal cyclic nucleotide binding (CNB-B) domain of PKGII binds cGMP with higher affinity and selectivity when compared with its N-terminal CNB (CNB-A) domain. To understand the structural basis of cGMP selectivity, we solved co-crystal structures of the CNB domains with cyclic nucleotides. Our structures combined with mutagenesis demonstrate that the guanine-specific contacts at Asp-412 and Arg-415more » of the αC-helix of CNB-B are crucial for cGMP selectivity and activation of PKG II. Structural comparison with the cGMP selective CNB domains of human PKG I and Plasmodium falciparum PKG (PfPKG) shows different contacts with the guanine moiety, revealing a unique cGMP selectivity mechanism for PKG II.« less
  • The presence of components of the renin-angiotensin system in ovaries and testes suggests that angiotensin II (AII) is involved in gonadal function, and thus we sought to characterize receptors for AII in rat and primate gonads. In the testes, autoradiographic studies showed receptors in the interstitium in all species. In rat interstitial cells fractionated by Percoll gradient, AII receptors coincided with hCG receptors indicating that AII receptors are located on the Leydig cells. In Leydig cells and membranes from rat and rhesus monkey prepuberal testes, AII receptors were specific for AII analogues and of high affinity (Kd=nM). During development, AIImore » receptor content in rat testes decreases with age parallel to a fall in the ratio of interstitial to tubular tissue. In the ovary, the distribution of AII receptors was dependent on the stage of development, being high in the germinal epithelium and stromal tissue between five and 15 days, and becoming localized in secondary follicles in 20-and 40-day-old rats. No binding was found in primordial or primary follicles. In rhesus monkey ovary, AII receptors were higher in stromal tissue and lower in granulosa and luteal cells of the follicles. Characterization of the binding in rat and monkey ovarian membranes showed a single class of sites with a Kd in the nmol/L range and specificity similar to that of the adrenal glomerulosa and testicular AII receptors. Receptors for AII were also present in membrane fractions from PMSG/hCG primed rat ovaries. Infusion of AII (25 ng/min) or captopril (1.4 micrograms/min) during the PMSG/hCG induction period had no effect on ovarian weight or AII receptor concentration in the ovaries.« less