Crystal Structure of a Multi-Domain Human Smoothened Receptor in Complex With a Super Stabilizing Ligand

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Description

The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by

The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.

Date Created
2017-05-17
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Network capacity assessment of CHP-based distributed generation on urban energy distribution networks

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Description
The combined heat and power (CHP)-based distributed generation (DG) or dis-tributed energy resources (DERs) are mature options available in the present energy mar-ket, considered to be an effective solution to promote energy efficiency. In the urban en-vironment, the electricity, water

The combined heat and power (CHP)-based distributed generation (DG) or dis-tributed energy resources (DERs) are mature options available in the present energy mar-ket, considered to be an effective solution to promote energy efficiency. In the urban en-vironment, the electricity, water and natural gas distribution networks are becoming in-creasingly interconnected with the growing penetration of the CHP-based DG. Subse-quently, this emerging interdependence leads to new topics meriting serious consideration: how much of the CHP-based DG can be accommodated and where to locate these DERs, and given preexisting constraints, how to quantify the mutual impacts on operation performances between these urban energy distribution networks and the CHP-based DG. The early research work was conducted to investigate the feasibility and design methods for one residential microgrid system based on existing electricity, water and gas infrastructures of a residential community, mainly focusing on the economic planning. However, this proposed design method cannot determine the optimal DG sizing and sit-ing for a larger test bed with the given information of energy infrastructures. In this con-text, a more systematic as well as generalized approach should be developed to solve these problems. In the later study, the model architecture that integrates urban electricity, water and gas distribution networks, and the CHP-based DG system was developed. The pro-posed approach addressed the challenge of identifying the optimal sizing and siting of the CHP-based DG on these urban energy networks and the mutual impacts on operation per-formances were also quantified. For this study, the overall objective is to maximize the electrical output and recovered thermal output of the CHP-based DG units. The electrici-ty, gas, and water system models were developed individually and coupled by the devel-oped CHP-based DG system model. The resultant integrated system model is used to constrain the DG's electrical output and recovered thermal output, which are affected by multiple factors and thus analyzed in different case studies. The results indicate that the designed typical gas system is capable of supplying sufficient natural gas for the DG normal operation, while the present water system cannot support the complete recovery of the exhaust heat from the DG units.
Date Created
2013
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