02148nas a2200169 4500008004100000022001400041245011300055210006900168260007900237300001400316490000800330520144400338100002101782700002801803700002001831856012701851 2014 eng d a0006-349500aCholesterol modulates the dimer interface of the beta(2)-adrenergic receptor via cholesterol occupancy sites0 aCholesterol modulates the dimer interface of the beta2adrenergic a600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USAbCELL PRESScMAR a1290-13000 v1063 a

The beta(2)-adrenergic receptor is an important member of the G-protein-coupled receptor (GPCR) superfamily, whose stability and function are modulated by membrane cholesterol. The recent high-resolution crystal structure of the beta(2)-adrenergic receptor revealed the presence of possible cholesterol-binding sites in the receptor. However, the functional relevance of cholesterol binding to the receptor remains unexplored. We used MARTINI coarse-grained molecular-dynamics simulations to explore dimerization of the beta(2)-adrenergic receptor in lipid bilayers containing cholesterol. A novel (to our knowledge) aspect of our results is that receptor dimerization is modulated by membrane cholesterol. We show that cholesterol binds to transmembrane helix IV, and cholesterol occupancy at this site restricts its involvement at the dimer interface. With increasing cholesterol concentration, an increased presence of transmembrane helices I and II, but a reduced presence of transmembrane helix IV, is observed at the dimer interface. To our knowledge, this study is one of the first to explore the correlation between cholesterol occupancy and GPCR organization. Our results indicate that dimer plasticity is relevant not just as an organizational principle but also as a subtle regulatory principle for GPCR function. We believe these results constitute an important step toward designing better drugs for GPCR dimer targets.

1 aPrasanna, Xavier1 aChattopadhyay, Amitabha1 aSengupta, Durba uhttps://library.ncl.res.in/content/cholesterol-modulates-dimer-interface-beta2-adrenergic-receptor-cholesterol-occupancy-001742nas a2200169 4500008004100000022001400041245006700055210006600122260009000188300001000278490000600288520111000294100002101404700002001425700002801445856009901473 2016 eng d a2045-232200aCholesterol-dependent conformational plasticity in GPCR dimers0 aCholesteroldependent conformational plasticity in GPCR dimers aMACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLANDbNATURE PUBLISHING GROUPcAUG a318580 v63 a

The organization and function of the serotonin1A receptor, an important member of the GPCR family, have been shown to be cholesterol-dependent, although the molecular mechanism is not clear. We performed a comprehensive structural and dynamic analysis of dimerization of the serotonin1A receptor by coarse-grain molecular dynamics simulations totaling 3.6 ms to explore the molecular details of its cholesterol-dependent association. A major finding is that the plasticity and flexibility of the receptor dimers increase with increased cholesterol concentration. In particular, a dimer interface formed by transmembrane helices I-I was found to be sensitive to cholesterol. The modulation of dimer interface appears to arise from a combination of direct cholesterol occupancy and indirect membrane effects. Interestingly, the presence of cholesterol at the dimer interface is correlated with increased dimer plasticity and flexibility. These results represent an important step in characterizing the molecular interactions in GPCR organization with potential relevance to therapeutic interventions.

1 aPrasanna, Xavier1 aSengupta, Durba1 aChattopadhyay, Amitabha uhttps://library.ncl.res.in/content/cholesterol-dependent-conformational-plasticity-gpcr-dimers00639nas a2200157 4500008004100000022001400041245008000055210006900135260008000204300001400284490000800298100002000306700002100326700002800347856010600375 2016 eng d a0006-349500aConformational dynamics of GPCR dimers is dependent on membrane cholesterol0 aConformational dynamics of GPCR dimers is dependent on membrane  a600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USAbBiophys SoccFEB a356A-356A0 v1101 aSengupta, Durba1 aPrasanna, Xavier1 aChattopadhyay, Amitabha uhttps://library.ncl.res.in/content/conformational-dynamics-gpcr-dimers-dependent-membrane-cholesterol02387nas a2200157 4500008004100000245011200041210006900153260000800222490000700230520177700237100002202014700001802036700002802054700002002082856012702102 2021 eng d00aConformational plasticity and dynamic interactions of the N-terminal domain of the chemokine receptor CXCR10 aConformational plasticity and dynamic interactions of the Ntermi cMAY0 v173 a

The dynamic interactions between G protein-coupled receptors (GPCRs) and their cognate protein partners are central to several cell signaling pathways. For example, the association of CXC chemokine receptor 1 (CXCR1) with its cognate chemokine, interleukin-8 (IL8 or CXCL8) initiates pathways leading to neutrophil-mediated immune responses. The N-terminal domain of chemokine receptors confers ligand selectivity, but unfortunately the conformational dynamics of this intrinsically disordered region remains unresolved. In this work, we have explored the interaction of CXCR1 with IL8 by microsecond time scale coarse-grain simulations, complemented by atomistic models and NMR chemical shift predictions. We show that the conformational plasticity of the apo-receptor N-terminal domain is restricted upon ligand binding, driving it to an open C-shaped conformation. Importantly, we corroborated the dynamic complex sampled in our simulations against chemical shift perturbations reported by previous NMR studies and show that the trends are similar. Our results indicate that chemical shift perturbation is often not a reporter of residue contacts in such dynamic associations. We believe our results represent a step forward in devising a strategy to understand intrinsically disordered regions in GPCRs and how they acquire functionally important conformational ensembles in dynamic protein-protein interfaces.

1 aKharche, Shalmali1 aJoshi, Manali1 aChattopadhyay, Amitabha1 aSengupta, Durba uhttps://library.ncl.res.in/content/conformational-plasticity-and-dynamic-interactions-n-terminal-domain-chemokine-receptor