Harlos K

References (3)

Title : Structural Analysis and Development of Notum Fragment Screening Hits - Zhao_2022_ACS.Chem.Neurosci_13_2060
Author(s) : Zhao Y , Mahy W , Willis NJ , Woodward HL , Steadman D , Bayle ED , Atkinson BN , Sipthorp J , Vecchia L , Ruza RR , Harlos K , Jeganathan F , Constantinou S , Costa A , Kjaer S , Bictash M , Salinas PC , Whiting P , Vincent JP , Fish PV , Jones EY
Ref : ACS Chem Neurosci , 13 :2060 , 2022
Abstract : The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 microM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC(50) 0.0067 microM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.
ESTHER : Zhao_2022_ACS.Chem.Neurosci_13_2060
PubMedSearch : Zhao_2022_ACS.Chem.Neurosci_13_2060
PubMedID: 35731924
Gene_locus related to this paper: human-NOTUM

Title : Structural basis for cell surface patterning through NetrinG-NGL interactions - Seiradake_2011_EMBO.J_30_4479
Author(s) : Seiradake E , Coles CH , Perestenko PV , Harlos K , McIlhinney RA , Aricescu AR , Jones EY
Ref : EMBO Journal , 30 :4479 , 2011
Abstract : Brain wiring depends on cells making highly localized and selective connections through surface protein-protein interactions, including those between NetrinGs and NetrinG ligands (NGLs). The NetrinGs are members of the structurally uncharacterized netrin family. We present a comprehensive crystallographic analysis comprising NetrinG1-NGL1 and NetrinG2-NGL2 complexes, unliganded NetrinG2 and NGL3. Cognate NetrinG-NGL interactions depend on three specificity-conferring NetrinG loops, clasped tightly by matching NGL surfaces. We engineered these NGL surfaces to implant custom-made affinities for NetrinG1 and NetrinG2. In a cellular patterning assay, we demonstrate that NetrinG-binding selectivity can direct the sorting of a mixed population of NGLs into discrete cell surface subdomains. These results provide a molecular model for selectivity-based patterning in a neuronal recognition system, dysregulation of which is associated with severe neuropsychological disorders.
ESTHER : Seiradake_2011_EMBO.J_30_4479
PubMedSearch : Seiradake_2011_EMBO.J_30_4479
PubMedID: 21946559

Title : Crystal structure of the GluR2 amino-terminal domain provides insights into the architecture and assembly of ionotropic glutamate receptors - Clayton_2009_J.Mol.Biol_392_1125
Author(s) : Clayton A , Siebold C , Gilbert RJ , Sutton GC , Harlos K , McIlhinney RA , Jones EY , Aricescu AR
Ref : Journal of Molecular Biology , 392 :1125 , 2009
Abstract : Ionotropic glutamate receptors are functionally diverse but have a common architecture, including the 400-residue amino-terminal domain (ATD). We report a 1.8-A resolution crystal structure of human GluR2-ATD. This dimeric structure provides a mechanism for how the ATDs can drive receptor assembly and subtype-restricted composition. Lattice contacts in a 4.1-A resolution crystal form reveal a tetrameric (dimer-dimer) arrangement consistent with previous cellular and cryo-electron microscopic data for full-length AMPA receptors.
ESTHER : Clayton_2009_J.Mol.Biol_392_1125
PubMedSearch : Clayton_2009_J.Mol.Biol_392_1125
PubMedID: 19651138