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This book is a passionate account of the scientific breakthroughs that led to the solution of the first protein structures and to the understanding of their function at atomic resolution. The book is divided into self-standing chapters that each deal with a protein or protein family. The subject is presented in a fluid, non-technical style that will engage student and scientists in biochemistry, biophysics, molecular and structure biology and physiology.

This book provides a molecular view of membrane transport by means of numerous biochemical and biophysical techniques. The rapidly growing numbers of atomic structures of transporters in different conformations and the constant progress in bioinformatics have recently added deeper insights. The unifying mechanism of energized solute transport across membranes is assumed to consist of the conformational cycling of a carrier protein to provide access to substrate binding sites from either side of a cellular membrane. Due to the central role of active membrane transport there is considerable interest in deciphering the principles of one of the most fundamental processes in nature: the alternating access mechanism. This book brings together particularly significant structure-function studies on a variety of carrier systems from different transporter families: Glutamate symporters, LeuT-like fold transporters, MFS transporters and SMR (RND) exporters, as well as ABC-type importers. The selected examples impressively demonstrate how the combination of functional analysis, crystallography, investigation of dynamics and computational studies has made it possible to create a conclusive picture or more precisely, “a molecular movie”. Although we are still far from a complete molecular description of the alternating access mechanism, remarkable progress has been made from static snapshots towards membrane transport dynamics.

Transporters in Drug Development examines how membrane transporters can be dealt with in academic–industrial drug discovery and pharmaceutical development as well as from a regulatory perspective. The book describes methods and examples of in vitro characterization of single transporters in the intestines, liver and kidneys as well as characterization of substrate overlap between various transporters. Furthermore, probes and biomarkers are suggested for studies of the transporters'impact on the pharmacokinetics of drug substrates/candidates interacting on transporters. The challenges of translating in vitro observed interaction of transporters into in vivo relevance are explored, and the book highlights perspectives of applying targeted proteomics and mechanistic modeling in this process.

The purpose of Ligand Efficiency Indices for Drug Discovery: Towards an Atlas-Guided Paradigm is to introduce in a concise and self-contained form the concepts, ideas, applications and examples of efficiency-driven drug discovery to the biomedical community at large. The book emphasizes the use of'new variables'and more objective numerical methods to drive drug discovery in an encompassing way. These'new variables'are based on Ligand Efficiency Indices (LEIs) formulated in a way that permits mapping Chemico-Biological Space (CBS) in an Atlas-like representation. It provides a practical and timely discussion of the concepts, ideas, applications and examples of efficiency-driven drug discovery. This book emphasizes the use of a graphical representation and objective numerical methods to drive drug discovery more effectively. It presents the definition of LEIs and the corresponding efficiency planes within an atlas-like environment to provide a robust graphical and numerical framework for medicinal chemists and drug-discoverers. - Provides a practical and timely discussion of the concepts, ideas, applications and examples of efficiency-driven drug discovery - Emphasizes the use of'new variables'and more objective numerical methods to drive quicker and more effective drug discovery - Presents the definition of Ligand Efficiency Indices (LEIs) and the corresponding efficiency planes as key concepts to provide a graphical and numerical framework

Lactoferrin is an iron-binding glycoprotein belonging to the transferrin family. It acts as a defense in host animals against microbes and viruses, since it has a broad spectrum of antimicrobial and antiviral activities. Lactoferrin has been shown to regulate the growth and differentiation of many types of cells. The results of recent studies indicate that lactoferrin is a potent regulator of dermal fibroblasts, and promotes cutaneous wound healing. The collagen gel contraction, a model of wound contraction during wound healing process, and migration of human fibroblasts were enhanced by lactoferrin. LRP-1 (LDL Receptor related Protein-1) acts as a signaling receptor for lactoferrin that mediate fibroblast response to lactoferrin by activating ERK/MAPK signaling pathway. In addition, lactoferrin promotes biosynthesis of extracellular matrix (ECM) component such as type-I collagen and hyaluronan. Hyaluronan is a major component of ECM in connective tissue and promotes wound healing. The promoting effect of lactoferrin on hyaluronan production was accompanied by promotion of HAS2 (hyaluronan synthase 2) expression. These observations suggest that lactoferrin promotes the wound healing by providing an ECM that promotes fibroblast migration. Lactoferrin is also known for its anti-inflammatory and immune modulating properties. According to recent in vivo study, lactoferrin promotes wound repair by promoting the early inflammatory phase of wound healing. Based on this, recombinant human lactoferrin was subsequently tested clinically in a Phase II trial in patients with diabetic ulcers and was found to be effective. Lactoferrin should be further evaluated in patients with diabetic and other types of ulcers.

It is increasingly recognized that various transporter proteins are expressed throughout the body and determine absorption, tissue distribution, biliary and renal elimination of endogenous compounds and drugs and drug effects. This book will give an overview on the transporter families which are most important for drug therapy. Most chapters will focus on one transporter family highlighting tissue expression, substrates, inhibitors, knock-out mouse models and clinical studies.

Multiple Equilibria in Proteins covers the multiple interactions between small ions and molecules and a protein molecule. The book also deals with the physicochemical mechanisms of this interaction and the information about protein structure and the forces stabilizing that structure. The text discusses the mathematical description of complex formation, the thermodynamic analysis of binding data, and various theoretical models which can be used to describe the phenomena of small molecule-macromolecule interactions. The measurement of complex formation; the binding of neutral molecules; and hydrogen-ion equilibria are also considered. The book further tackles metal-ion binding; the binding of organic ions by proteins; as well as protein-protein interaction. Chemists and biochemists will find the book useful.