title: Structural role of the T94I rhodopsin mutation in congenital stationary night blindness.
abstract: Congenital stationary night blindness (CSNB) is an inherited and non-progressive retinal dysfunction. Here, we present the crystal structure of CSNB-causing T94I2.61rhodopsin in the active conformation at 2.3 Å resolution. The introduced hydrophobic side chain prolongs the lifetime of the G protein activating metarhodopsin-II state by establishing a direct van der Waals contact with K2967.43, the site of retinal attachment. This is in stark contrast to the light-activated state of the CSNB-causing G90D2.57mutation, where the charged mutation forms a salt bridge with K2967.43To find the common denominator between these two functional modifications, we combined our structural data with a kinetic biochemical analysis and molecular dynamics simulations. Our results indicate that both the charged G90D2.57and the hydrophobic T94I2.61mutation alter the dark state by weakening the interaction between the Schiff base (SB) and its counterion E1133.28We propose that this interference with the tight regulation of the dim light photoreceptor rhodopsin increases background noise in the visual system and causes the loss of night vision characteristic for CSNB patients.
authors.affiliation: Division of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Ankita
authors.initials: A
authors.lastname: Singhal
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Division of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Milos
authors.initials: M
authors.lastname: Matkovic
authors.affiliation: Division of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland Deparment of Biology, ETH Zurich, Zürich, Switzerland.
authors.forename: Gebhard
authors.initials: G
authors.lastname: Schertler
authors.affiliation: Division of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland Condensed Matter Theory Group, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT, USA.
authors.forename: Elsa Cy
authors.initials: EC
authors.lastname: Yan
authors.affiliation: Division of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland joerg.standfuss@psi.ch.
authors.forename: Joerg
authors.identifier: 0000-0001-8825-386X
authors.initials: J
authors.lastname: Standfuss
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003624:Darkness; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D009216:Myopia / Q000235:genetics*; D009755:Night Blindness / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D012243:Rhodopsin / Q000737:chemistry* / Q000235:genetics*; D012545:Schiff Bases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D012545:Schiff Bases; D012243:Rhodopsin
keywords: G protein‐coupled receptors; congenital stationary night blindness; constitutive activity; rhodopsin; visual system