title: Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints.
abstract: Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors.
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden. Electronic address: karl.edman@astrazeneca.com.
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Ali
authors.initials: A
authors.lastname: Hosseini
authors.affiliation: R&D Information, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Magnus K
authors.initials: MK
authors.lastname: Bjursell
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Aagaard
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wissler
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Gunnarsson
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Tim
authors.initials: T
authors.lastname: Kaminski
authors.affiliation: RIA, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Köhler
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bäckström
authors.affiliation: RIA, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Tina J
authors.initials: TJ
authors.lastname: Jensen
authors.affiliation: RIA, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Cavallin
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Karlsson
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Ewa
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lecina
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: CVMD, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Grebner
authors.affiliation: Discovery Sciences, AstraZeneca, Mölndal, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.affiliation: RIA, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Lepistö
authors.affiliation: CVMD, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden. Electronic address: anders.hogner@astrazeneca.com.
authors.forename: Anders C
authors.initials: AC
authors.lastname: Hogner
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain. Electronic address: victor.guallar@bsc.es.
authors.forename: Victor
authors.initials: V
authors.lastname: Guallar
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid