Mechanisms of Molecular Recognition: Crystal Structure Analysis of Human and Rat Transthyretin Inhibitor Complexes
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Vivian Cody
Abstract
Structure-activity data show that many pharmacological agents are strong competitive inhibitors for thyroxine (T4) binding to transthyretin (TTR) and that this competition can interfere with their normal pharmacological actions. TTR is a tetrameric serum protein responsible for the transport of 20% of the circulating T4 in man, while in lower vertebrates such as rats it is the only carrier. The sequence of rat TTR is 85% homologous to the human protein. Crystallographic analyses of ligand co-crystal complexes of human and rat TTR have been studied to understand the molecular basis for binding selectivity of competitor binding to TTR. Analysis of TTR crystal complexes with several classes of competitors (hormone metabolites, flavonoids, fluorescent probes, analgesics and cardiac agents) revealed multiple modes of binding with both forward and reverse ligand binding orientations. These ligands also have different binding positions along the length of the channel with the smallest ligands located deeper within the hormone domain. Data for the human TTR complex with the bromoflavone EMD21388 incubated at different times revealed variable binding positions and occupancies dependent upon incubation time. Comparison of the structures of T4 thyroacetic acid in complex with both human and rat TTR revealed forward and reverse binding, but also showed different modes of binding in the rat compared to the human complex. These data highlight the importance of hydrogen bonding with Lys-15 and Ser-117 and provide insight into ligand binding affinity and negative cooperativity.
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
Articles in the same Issue
- Author Index
- Subject Index
- Contents
- Historical Aspects and Perspectives in Transthyretin Research
- Transthyretin from Discovery to Now
- The Evolution of Transthyretin Synthesis in Vertebrate Liver, in Primitive Eukaryotes and in Bacteria
- The Evolution of Transthyretin Synthesis in the Choroid Plexus
- Hepatic Synthesis, Maturation and Complex Formation between Retinol-Binding Protein and Transthyretin
- Synthesis and Structural Analysis of the N-Terminal Domain of the Thyroid Hormone-Binding Protein Transthyretin
- Three-Dimensional Structure of the Transthyretin-Retinol-Binding Protein Complex
- Mechanisms of Molecular Recognition: Crystal Structure Analysis of Human and Rat Transthyretin Inhibitor Complexes
- Transthyretin in Fish: State of the Art
- The Effects of Endocrine-Disrupting Chemicals on Thyroid Hormone Binding to Xenopus laevis Transthyretin and Thyroid Hormone Receptor
- Clinical Picture and Outcome of Transthyretin-Related Familial Amyloid Polyneuropathy (FAP) in Japanese Patients
- Laboratory Assessment of Transthyretin Amyloidosis
- Amyloid: Morphology and Toxicity
- Historical Overview of Analytical Methods for the Measurement of Transthyretin
- Nutritional Regulation of Visceral Markers in Rat Liver and Cultured Hepatoma Cells
- Significance of Transthyretin in Protein Metabolism
- Transthyretin as a Thyroid Hormone Carrier: Function Revisited
- The Molar Ratio of Retinol-Binding Protein to Transthyretin in the Assessment of Vitamin A Status in Adults. Proposal of a Cut-off Point
- Observations with Regard to the National Kidney Foundation K/DOQI Clinical Practice Guidelines Concerning Serum Transthyretin in Chronic Renal Failure
- Metabolism and Clinical Interest of Serum Transthyretin (Prealbumin) in Dialysis Patients
- Protein Status in Pancreatitis – Transthyretin Is a Sensitive Biomarker of Malnutrition in Acute and Chronic Pancreatitis
- Assessment of Nutritional Status in Organ Transplant: Is Transthyretin a Reliable Indicator?
- Body Composition and Nutritional Parameters in HIV and AIDS Patients
- C-Reactive Protein to Transthyretin Ratio for the Early Diagnosis and Follow-up of Postoperative Infection
- The Prognostic Value of Nutritional and Inflammatory Indices in Critically Ill Patients with Acute Respiratory Failure
- Transthyretin: Its Response to Malnutrition and Stress Injury. Clinical Usefulness and Economic Implications
- Transthyretin Measurement as a Screening Tool for Protein Calorie Malnutrition in Emergency Hospital Admissions
- Outcomes of Continuous Process Improvement of a Nutritional Care Program Incorporating TTR Measurement
- The Role of Visceral Protein Markers in Protein Calorie Malnutrition
- Acknowledgement
- Meetings
Articles in the same Issue
- Author Index
- Subject Index
- Contents
- Historical Aspects and Perspectives in Transthyretin Research
- Transthyretin from Discovery to Now
- The Evolution of Transthyretin Synthesis in Vertebrate Liver, in Primitive Eukaryotes and in Bacteria
- The Evolution of Transthyretin Synthesis in the Choroid Plexus
- Hepatic Synthesis, Maturation and Complex Formation between Retinol-Binding Protein and Transthyretin
- Synthesis and Structural Analysis of the N-Terminal Domain of the Thyroid Hormone-Binding Protein Transthyretin
- Three-Dimensional Structure of the Transthyretin-Retinol-Binding Protein Complex
- Mechanisms of Molecular Recognition: Crystal Structure Analysis of Human and Rat Transthyretin Inhibitor Complexes
- Transthyretin in Fish: State of the Art
- The Effects of Endocrine-Disrupting Chemicals on Thyroid Hormone Binding to Xenopus laevis Transthyretin and Thyroid Hormone Receptor
- Clinical Picture and Outcome of Transthyretin-Related Familial Amyloid Polyneuropathy (FAP) in Japanese Patients
- Laboratory Assessment of Transthyretin Amyloidosis
- Amyloid: Morphology and Toxicity
- Historical Overview of Analytical Methods for the Measurement of Transthyretin
- Nutritional Regulation of Visceral Markers in Rat Liver and Cultured Hepatoma Cells
- Significance of Transthyretin in Protein Metabolism
- Transthyretin as a Thyroid Hormone Carrier: Function Revisited
- The Molar Ratio of Retinol-Binding Protein to Transthyretin in the Assessment of Vitamin A Status in Adults. Proposal of a Cut-off Point
- Observations with Regard to the National Kidney Foundation K/DOQI Clinical Practice Guidelines Concerning Serum Transthyretin in Chronic Renal Failure
- Metabolism and Clinical Interest of Serum Transthyretin (Prealbumin) in Dialysis Patients
- Protein Status in Pancreatitis – Transthyretin Is a Sensitive Biomarker of Malnutrition in Acute and Chronic Pancreatitis
- Assessment of Nutritional Status in Organ Transplant: Is Transthyretin a Reliable Indicator?
- Body Composition and Nutritional Parameters in HIV and AIDS Patients
- C-Reactive Protein to Transthyretin Ratio for the Early Diagnosis and Follow-up of Postoperative Infection
- The Prognostic Value of Nutritional and Inflammatory Indices in Critically Ill Patients with Acute Respiratory Failure
- Transthyretin: Its Response to Malnutrition and Stress Injury. Clinical Usefulness and Economic Implications
- Transthyretin Measurement as a Screening Tool for Protein Calorie Malnutrition in Emergency Hospital Admissions
- Outcomes of Continuous Process Improvement of a Nutritional Care Program Incorporating TTR Measurement
- The Role of Visceral Protein Markers in Protein Calorie Malnutrition
- Acknowledgement
- Meetings
