3 research outputs found
Solution Structure of CCL21 and Identification of a Putative CCR7 Binding Site
CCL21 is a human chemokine that recruits normal immune
cells and
metastasizing tumor cells to lymph nodes through activation of the
G protein-coupled receptor CCR7. The CCL21 structure solved by NMR
contains a conserved chemokine domain followed by an extended, unstructured
C-terminus that is not typical of most other chemokines. A sedimentation
equilibrium study showed CCL21 to be monomeric. Chemical shift mapping
indicates that the CCR7 N-terminus binds to the N-loop and third β-strand
of CCL21’s chemokine domain. Details of CCL21-receptor recognition
may enable structure-based drug discovery of novel antimetastatic
agents
A Rationally Designed Agonist Defines Subfamily IIIA Abscisic Acid Receptors As Critical Targets for Manipulating Transpiration
Increasing drought
and diminishing freshwater supplies have stimulated
interest in developing small molecules that can be used to control
transpiration. Receptors for the plant hormone abscisic acid (ABA)
have emerged as key targets for this application, because ABA controls
the apertures of stomata, which in turn regulate transpiration. Here,
we describe the rational design of cyanabactin, an ABA receptor agonist
that preferentially activates <i>Pyrabactin Resistance 1</i> (PYR1) with low nanomolar potency. A 1.63 Ă… X-ray crystallographic
structure of cyanabactin in complex with PYR1 illustrates that cyanabactin’s
arylnitrile mimics ABA’s cyclohexenone oxygen and engages the
tryptophan lock, a key component required to stabilize activated receptors.
Further, its sulfonamide and 4-methylbenzyl substructures mimic ABA’s
carboxylate and C6 methyl groups, respectively. Isothermal titration
calorimetry measurements show that cyanabactin’s compact structure
provides ready access to high ligand efficiency on a relatively simple
scaffold. Cyanabactin treatments reduce <i>Arabidopsis</i> whole-plant stomatal conductance and activate multiple ABA responses,
demonstrating that its <i>in vitro</i> potency translates
to ABA-like activity <i>in vivo</i>. Genetic analyses show
that the effects of cyanabactin, and the previously identified agonist
quinabactin, can be abolished by the genetic removal of PYR1 and PYL1,
which form subclade A within the dimeric subfamily III receptors.
Thus, cyanabactin is a potent and selective agonist with a wide spectrum
of ABA-like activities that defines subfamily IIIA receptors as key
target sites for manipulating transpiration
A Rationally Designed Agonist Defines Subfamily IIIA Abscisic Acid Receptors As Critical Targets for Manipulating Transpiration
Increasing drought
and diminishing freshwater supplies have stimulated
interest in developing small molecules that can be used to control
transpiration. Receptors for the plant hormone abscisic acid (ABA)
have emerged as key targets for this application, because ABA controls
the apertures of stomata, which in turn regulate transpiration. Here,
we describe the rational design of cyanabactin, an ABA receptor agonist
that preferentially activates <i>Pyrabactin Resistance 1</i> (PYR1) with low nanomolar potency. A 1.63 Ă… X-ray crystallographic
structure of cyanabactin in complex with PYR1 illustrates that cyanabactin’s
arylnitrile mimics ABA’s cyclohexenone oxygen and engages the
tryptophan lock, a key component required to stabilize activated receptors.
Further, its sulfonamide and 4-methylbenzyl substructures mimic ABA’s
carboxylate and C6 methyl groups, respectively. Isothermal titration
calorimetry measurements show that cyanabactin’s compact structure
provides ready access to high ligand efficiency on a relatively simple
scaffold. Cyanabactin treatments reduce <i>Arabidopsis</i> whole-plant stomatal conductance and activate multiple ABA responses,
demonstrating that its <i>in vitro</i> potency translates
to ABA-like activity <i>in vivo</i>. Genetic analyses show
that the effects of cyanabactin, and the previously identified agonist
quinabactin, can be abolished by the genetic removal of PYR1 and PYL1,
which form subclade A within the dimeric subfamily III receptors.
Thus, cyanabactin is a potent and selective agonist with a wide spectrum
of ABA-like activities that defines subfamily IIIA receptors as key
target sites for manipulating transpiration