Molecular basis of ligand recognition and activation of human V2 vasopressin receptor.

Vasopressin type 2 receptor (V2R) belongs to the vasopressin (VP)/oxytocin (OT) receptor subfamily of G protein-coupled receptors (GPCRs), which comprises at least four closely related receptor subtypes: V1aR, V1bR, V2R, and OTR. These receptors are activated by arginine vasopressin (AVP) and OT, two endogenous nine-amino acid neurohypophysial hormones, which are thought to mediate a biologically conserved role in social behavior and sexual reproduction. V2R is mainly expressed in the renal collecting duct principal cells and mediates the antidiuretic action of AVP by accelerating water reabsorption, thereby playing a vital role in controlling water homeostasis. Moreover, numerous gain-of-function and loss-of-function mutations of V2R have been identified and are closely associated with human diseases, including nephrogenic syndrome of inappropriate diuresis (NSIAD) and X-linked congenital nephrogenic diabetes insipidus (NDI). Thus, V2R has attracted intense interest as a drug target. However, due to a lack of structural information, how AVP recognizes and activates V2R remains elusive, which hampers the V2R-targeted drug design. Here, we determined a 2.6 Å resolution cryo-EM structure of the full-length, G s -coupled human V2R bound to AVP (Fig. 1a; Supplementary information, Table S1). The G s protein was engineered based on mini-G s that was used in the crystal structure determination of the G s -coupled adenosine A 2A receptor (A 2A R) to stabilize the V2R–G s protein complex (Supplementary information, Data S1). The final structure of the AVP–V2R–G s complex contains all residues of AVP (residues 1–9), the Gα s Ras-like domain, Gβγ subunits, Nb35, scFv16, and the V2R residues from T31 to L339 8.57 (superscripts refer to Ballesteros–Weinstein numbering). The majority of amino acid side chains, including AVP, transmembrane domain (TMD), all flexible intracellular loops (ICLs) and extracellular loops (ECLs) except for ICL3 and G185–G188 in ECL2, were well resolved in the model, refined against the EM density map (Fig. 1a; Supplementary information, Figs. S1–3). The complex structure can provide detailed information on the binding interface between AVP and helix bundle of the receptor, as well as the receptor–G s interface

Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor.

Cholecystokinin A receptor (CCKAR) belongs to family A G-protein-coupled receptors and regulates nutrient homeostasis upon stimulation by cholecystokinin (CCK). It is an attractive drug target for gastrointestinal and metabolic diseases. One distinguishing feature of CCKAR is its ability to interact with a sulfated ligand and to couple with divergent G-protein subtypes, including Gs, Gi and Gq. However, the basis for G-protein coupling promiscuity and ligand recognition by CCKAR remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCKAR in complex with Gs, Gi and Gq heterotrimers, respectively. CCKAR presents a similar conformation in the three structures, whereas conformational differences in the 'wavy hook' of the Gα subunits and ICL3 of the receptor serve as determinants in G-protein coupling selectivity. Our findings provide a framework for understanding G-protein coupling promiscuity by CCKAR and uncover the mechanism of receptor recognition by sulfated CCK-8

Protolith ages and timing of peak and retrograde metamorphism of the high-pressure granulites in the Shandong Peninsula, eastern North China Craton

High-pressure (HP) granulites widely occur as enclaves within tonalite-trondhjemite-granodiorite (TTG) gneisses of the Early Precambrian metamorphic basement in the Shandong Peninsula, southeast part of the North China Craton (NCC). Based on cathodoluminescence (CL), laser Raman spectroscopy and in-situ U-Pb dating, we characterize the zircons from the HP granulites and group them into three main types: inherited (magmatic) zircon, HP metamorphic zircon and retrograde zircon. The inherited zircons with clear or weakly defined magmatic zoning contain inclusions of apatites, and 207Pb/206Pb ages of 2915–2890 Ma and 2763–2510 Ma, correlating with two magmatic events in the Archaean basement. The homogeneous HP metamorphic zircons contain index minerals of high-pressure metamorphism including garnet, clinopyroxene, plagioclase, quartz, rutile and apatite, and yield 207Pb/206Pb ages between 1900 and 1850 Ma, marking the timing of peak HP granulite facies metamorphism. The retrograde zircons contain inclusions of orthopyroxene, plagioclase, quartz, apatite and amphibole, and yield the youngest 207Pb/206Pb ages of 1840–1820 Ma among the three groups, which we correlate to the medium to low-pressure granulite facies retrograde metamorphism. The data presented in this study suggest subduction of Meso- and Neoarchean magmatic protoliths to lower crust depths where they were subjected to HP granulite facies metamorphism during Palaeoproterozoic (1900–1850 Ma). Subsequently, the HP granulites were exhumated to upper crust levels, and were overprinted by medium to low-pressure granulite and amphibolite facies retrograde event at ca. 1840–820 Ma

Iodine-Promoted Deoxygenative Iodization/Olefination/Sulfenylation of Ketones with Sulfonyl Hydrazides: Access to β‑Iodoalkenyl Sulfides

A highly regio- and stereoselective synthesis of β-haloalkenyl sulfides using commercially available ketones and sulfonyl hydrazides as starting materials has been developed. This protocol obviates the need for alkynes and traditional sulfenylating agents and therefore opens up a new door to construct β-iodoalkenyl sulfides in a highly simple manner. This study reveals that ketones could be used as vinyl iodide precursors in organic synthesis