Editorial—A Growing Partnership Between Structural Biology and Molecular Endocrinology

John H. Nilson

Molecular Endocrinology publishes manuscripts that provide new mechanistic insights into hormone action. With unprecedented access to sequences from the genomes of humans, rodents, and other model organisms, our field is rapidly turning to genomic approaches because these avenues offer a rich harvest of new information explaining the how and why of hormone action. In this regard, structural biology represents an important branch of the genomic revolution as it seeks to provide full coverage of protein sequence space, the structural culmination of information housed within the genome. In addition to providing mechanistic insights that will help explain the action of known hormones, the knowledge of one protein structure will spawn computational models that predict the structure of related proteins in which insufficient information was previously available. Likewise, knowledge of the structural biology that defines the function of one protein will be useful in predicting the function of both newly discovered proteins and established proteins in which this property was previously unknown. For molecular endocrinologists, it is becoming increasingly apparent that coupling structural biology with functional genomics will provide a wealth of new information that explains the mechanism of action of hormones.

Recognizing the growing relationship between structural biology and molecular endocrinology, we issued a call for papers last January that we hoped would explore the interface between these two disciplines. We are pleased to announce that, resulting from our invitation, this issue contains a special thematic section in which the relationship between protein structure and hormone action is further developed.

The structural biology theme begins with a Mini-Review by Michael Weiss, who has examined the relationship between the DNA-bending motifs in transcription proteins involved in sex determination. His observations suggest that these proteins lack a fixed tertiary structure and, furthermore, that their DNA-bending activity and subsequent stabilization of protein structure define a coupled process relevant to the configuration of promoter-specific architectures. Weiss and colleagues explore this notion further in a full paper where they have uncovered an activating mutation in the cantilever side chain of the HMG box of SRY. This mutation prolongs the lifetime of SRY on DNA without affecting its overall equilibrium properties. As a consequence, Weiss and colleagues propose a new mechanism of kinetic control whereby the "locked" DNA bend induced by SRY and its prolonged lifetime on DNA enables multiple rounds of transcription initiation per promoter. This model of kinetic control is interesting because it predicts occurrence of a novel class of clinical phenotypes.

The cover illustrates the crystal structure of human FSH containing a mutation that eliminates a specific glycosylation site without affecting its receptor binding and signal transduction activities. This mutation rendered the protein more suitable for crystallization. The overall head-to-tail arrangements of the two subunits of FSH are similar to that of human chorionic gonadotropin (hCG). In fact, detailed comparison of the two crystal structures reveals several differences that may be important to specificity of receptor binding and signal transduction. It is easy to foresee that exploiting these differences should lead to the development of more specific and more effective therapeutic agents.

Members of the rhodopsin family of G protein- coupled receptors contain an "arginine cage" motif at the cytoplasmic side of their third transmembrane domain. To examine the functional importance of the intrahelical position and orientation of the arginine cage, Sealfon and colleagues used insertional mutagenesis to alter this region in the GnRH receptor. Their characterization allows uncoupling of structural contributions important for stabilization of high-affinity receptor interactions from those required for efficient signaling. This ability to dissociate multiple activities associated with complex signaling pathways also has potential therapeutic relevance.

Two of our thematic papers address structural features of nuclear receptors. Gee and Katzenellenbogen capitalized on the intrinsic tryptophan fluorescence of ER{alpha} and ERß and used a chemical probe to better understand the envelopment of the ligand upon its binding to these receptors. Their experimental outcomes suggest a two-phase process whereby the unfolding of ER allows ligands to enter and exit the hormone-binding pocket.

Once in the binding pocket, steroids interact specifically with nuclear receptors. To further explore the basis of selectivity, Fletterick and colleagues determined the crystal structure of the ligand-binding domains of TR{alpha} and TRß when complexed with nonselective and selective ligands. Their work indicates subtle structural differences between the receptor subtypes that explain differences in selectivity and suggest a rational strategy for development of new subtype-specific compounds.

More than 12 distinct mutations of the Pit-I gene have been shown to be responsible for a clinical phenotype that manifests as combined pituitary hormone deficiency involving PRL, GH, and TSH. Most, if not all, of these mutations impair functional activity of Pit-1 without altering its ability to bind DNA. The paper by Brue and colleagues builds upon crystallographic analysis of DNA/Pit-1 POU domain complexes and uses molecular modeling to examine structural characteristics of three different mutations that occur at the same site in Pit-1. Their analysis suggests that conformational perturbations of the first helix in the POU-specific domain of Pit-1 preclude necessary interactions with additional transcriptional cofactors. This information will enhance future identification and characterization of the critical members of what is undoubtedly a complex transcriptional pathway.

While the papers described above successfully explore the growing interface between structural biology and molecular endocrinology, they represent only the beginning of a productive new relationship. We are hopeful that their publication will trigger submission of many more papers that use structural biology to explore hormone action. Likewise, in recognizing that structural biology is but one branch of the growing field of genomics, we are also hopeful that additional manuscripts covering this entire area will appear in our mailbox.





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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals