2 research outputs found
Three-Dimensional Structure of the <i>Rhodobacter sphaeroides</i> RC-LH1-PufX Complex: Dimerization and Quinone Channels Promoted by PufX
Reaction
center-light harvesting 1 (RC-LH1) complexes are the fundamental
units of bacterial photosynthesis, which use solar energy to power
the reduction of quinone to quinol prior to the formation of the proton
gradient that drives ATP synthesis. The dimeric RC-LH1-PufX complex
of Rhodobacter sphaeroides is composed
of 64 polypeptides and 128 cofactors, including 56 LH1 bacteriochlorophyll <i>a</i> (BChl <i>a</i>) molecules that surround and
donate energy to the two RCs. The 3D structure was determined to 8
Å by X-ray crystallography, and a model was built with constraints
provided by electron microscopy (EM), nuclear magnetic resonance (NMR),
mass spectrometry (MS), and site-directed mutagenesis. Each half of
the dimer complex consists of a RC surrounded by an array of 14 LH1
αβ subunits, with two BChls sandwiched between each αβ
pair of transmembrane helices. The N- and C-terminal extrinsic domains
of PufX promote dimerization by interacting with the corresponding
domains of an LH1 β polypeptide from the other half of the RC-LH1-PufX
complex. Close contacts between PufX, an LH1 αβ subunit,
and the cytoplasmic domain of the RC-H subunit prevent the LH1 complex
from encircling the RC and create a channel connecting the RC Q<sub>B</sub> site to an opening in the LH1 ring, allowing Q/QH<sub>2</sub> exchange with the external quinone pool. We also identified a channel
that connects the two halves of the dimer, potentially forming a long-range
pathway for quinone migration along rows of RC-LH1-PufX complexes
in the membrane. The structure of the RC-LH1-PufX complex explains
the crucial role played by PufX in dimer formation, and it shows how
quinone traffic traverses the LH1 complex as it shuttles between the
RC and the cytochrome <i>bc</i><sub>1</sub> complex
Discovery of 1,2,4-Triazine Derivatives as Adenosine A<sub>2A</sub> Antagonists using Structure Based Drug Design
Potent, ligand efficient, selective, and orally efficacious
1,2,4-triazine
derivatives have been identified using structure based drug design
approaches as antagonists of the adenosine A<sub>2A</sub> receptor.
The X-ray crystal structures of compounds <b>4e</b> and <b>4g</b> bound to the GPCR illustrate that the molecules bind deeply
inside the orthosteric binding cavity. In vivo pharmacokinetic and
efficacy data for compound <b>4k</b> are presented, demonstrating
the potential of this series of compounds for the treatment of Parkinson’s
disease