Table of Contents TABLE OF CONTENTS

written with the cooperation of the program authors Zbyszek Otwinowski and Wladek Mino

Structural basis of VDR–DNA interactions on direct repeat response elements

The vitamin D receptor (VDR) forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by 3 bp of spacer DNA. We describe here the crystal structures at 2.7–2.8 Å resolution of the VDR DNA-binding region (DBD) in complex with response elements from three different promoters: osteopontin (SPP), canonical DR3 and osteocalcin (OC). These structures reveal the chemical basis for the increased affinity of VDR for the SPP response element, and for the poor stability of the VDR–OC complex, relative to the canonical DR3 response element. The homodimeric protein–protein interface is stabilized by van der Waals interactions and is predominantly non-polar. An extensive α-helix at the C-terminal end of the VDR DBD resembles that found in the thyroid hormone receptor (TR), and suggests a mechanism by which VDR and TR discriminate among response elements. Selective structure-based mutations in the asymmetric homodimeric interface result in a VDR DBD protein that is defective in homodimerization but now forms heterodimers with the 9-cis retinoic acid receptor (RXR) DBD

Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer

Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, which impairs AR activation and leads to PCa regression. However, ADT is palliative and PCa recurs as castration-recurrent/resistant PCa (CRPC). One mechanism for PCa recurrence relies on intratumoral synthesis of DHT, which can be synthesized using the frontdoor or primary or secondary backdoor pathway. Androgen metabolism inhibitors, such as those targeting 5α-reductase, aldo-keto-reductase family member 3 (AKR1C3), or cytochrome P450 17A1 (CYP17A1) have either failed or produced only modest clinical outcomes. The goal of this review is to describe the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation. Keywords: Androstanediol, Dihydrotestosterone, Dutasteride, 3α-oxidoreductases, Androgen deprivation therapy, Abirateron

Altered Patterns of Word Associations in Dementia and Aphasia

The Word Associations of 38 Demented, 17 Aphasic, and 22 Normal Subjects Were Studied. Both Normal and Brain-Injured Subjects Appear to Make Judgments About the Grammatical Class of the Word Stimulus. Certain Stimulus Words (Especially Nouns and Adjectives) Elicit Paradigmatic Responses Whereas Other Words (Especially Verbs and Adverbs) Elicit Syntagmatic Responses. the Mechanism Producing Syntagmatic Responses Seems Relatively Resistant to Deterioration in Dementia or Aphasia. However, in Dementia the Mechanism that Generates Paradigmatic Responses Becomes Progressively Less Efficient (Possibly Due to a Loss of Semantic Markers) and Consequently More Random (Idiosyncratic) Responses Emerge. Perseverative Responses, Inhibited in Normal Subjects, Are More Prevalent in Dementia. Anomic Aphasics Show a Pattern of Word Associations Similar to that of Subjects with Mild Dementia. Broca\u27s Aphasics, While Making Fewer Paradigmatic Associations Than Normals, Retain Enough Self-Monitoring Mechanisms So that Few Idiosyncratic and Perseverative Responses Are Made While More Null Responses Occur. Wernicke\u27s Aphasics Show a Marked Shift Away from a Paradigmatic Word Association Strategy, Possibly Due to an Inability to Access Semantic Markers or a True Loss of These Markers. Metalinguistic Deficits (I.e., a Failure to Adopt an Appropriate Strategy) May Also Contribute to This Shift Away from Paradigmatic Associations. Furthermore, a Disruption of Self-Monitoring Mechanisms in Wernicke\u27s Aphasia Leads to an Increase in Perseverative and Idiosyncratic Responses. © 1984