Related Experiment Video
Updated: Apr 28, 2026
11:07
Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
Published on: September 21, 2011
14.3K
Historical contingency and its biophysical basis in glucocorticoid receptor evolution
Michael J Harms1, Joseph W Thornton2
11] Institute of Molecular Biology and Department of Chemistry &Biochemistry, University of Oregon, Eugene, Oregon 97403, USA [2] Departments of Human Genetics and Ecology &Evolution, University of Chicago, Chicago, Illinois 60637, USA.
Nature
|June 17, 2014
Summary
Evolutionary history was shaped by rare, chance events. Specific protein mutations, necessary for function changes in the ancestral glucocorticoid receptor (GR), were exceptionally uncommon due to biophysical constraints.
Area of Science:
- Evolutionary biology
- Molecular evolution
- Biophysics
Background:
- Understanding evolutionary contingency is key to evolutionary biology.
- Experimental systems offer limited insight into past evolutionary events.
- The evolution of novel protein functions often depends on historical chance events.
Purpose of the Study:
- To explore alternative evolutionary trajectories for a novel protein function.
- To investigate the rarity of permissive mutations in ancestral protein evolution.
- To determine the biophysical basis for the rarity of permissive mutations.
Main Methods:
- Ancestral protein reconstruction
- Directed evolution experiments
- Biophysical analysis of protein variants
Main Results:
- Alternative permissive mutations for ancestral glucocorticoid receptor (GR) evolution were extremely rare.
- Historical permissive substitutions were recovered, but no alternative permissive genotypes were found.
- Permissive mutations require stabilization of local structure, maintenance of energetic balance, and compatibility with ancestral and derived structures.
Conclusions:
- The evolution of cortisol specificity in ancestral GR was strongly dependent on improbable, non-deterministic events.
- The rarity of permissive mutations stems from intrinsic biophysical properties of the protein.
- Evolutionary contingency is influenced by inherent biophysical constraints on protein structure and function.
Related Concept Videos
01:19Cushing Syndrome II: Pathophysiology
22
Cortisol production is normally governed by the hypothalamic–pituitary–adrenal (HPA) axis, which maintains hormonal balance through tightly regulated feedback mechanisms. Disruption of this regulatory system is central to the development of Cushing syndrome, whether the excess cortisol originates from external medications or internal pathology. Persistent cortisol elevation alters metabolism, immune function, and endocrine signaling, producing the characteristic clinical features...
22
01:22Target Cell Response to Hormones
5.6K
Hormones intricately bind to receptors on the surface or within target cells, initiating a cascade of cellular responses.
Notably, the cellular response can be regulated by altering the number of receptors expressed in the cell. For example, prolonged exposure to elevated hormone levels results in a gradual decline or down-regulation in the number of receptors for that specific hormone on the cell surface. Conversely, in response to low hormone levels, cells may use up-regulation, producing an...
Notably, the cellular response can be regulated by altering the number of receptors expressed in the cell. For example, prolonged exposure to elevated hormone levels results in a gradual decline or down-regulation in the number of receptors for that specific hormone on the cell surface. Conversely, in response to low hormone levels, cells may use up-regulation, producing an...
5.6K
01:28Global Regulatory Systems
952
Global regulatory systems in bacteria enable rapid and coordinated responses to environmental changes by integrating sensory inputs with gene expression, ensuring efficient adaptation to fluctuating conditions. Key global regulatory mechanisms include regulons, two-component systems, sigma factors, and secondary messengers.Regulons and Global RegulatorsA regulon is a collection of genes and operons controlled by a common global regulator. These regulators enable bacteria to prioritize resource...
952
01:31Transducer Mechanism: Nuclear Receptors
6.5K
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
6.5K
01:29The Two-State Receptor Model
3.5K
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
The binding affinity of a drug determines its interaction with...
3.5K
01:16Transduction
3.0K
Among the three main modes of HGT—transformation, conjugation, and transduction—transduction is unique in that it is mediated by bacteriophages, or bacterial viruses.Transduction occurs in two ways. Generalized transduction occurs during the lytic cycle of a bacteriophage infection. In this process, bacteriophages infect bacterial cells, replicate within them, and ultimately cause cell lysis, releasing newly assembled virions. Occasionally, random fragments of the bacterial genome...
3.0K