Protein Structure: Determination, Analysis, And Applications For Drug Discovery

Protein Structure Determination, Analysis, and Applications for Drug Discovery edited by Daniel I. Chasman Variagenics, Inc. Cambridge, Massachusetts, U.S.A. MARCEL MARCELDEKKER, INC. DLKKER NEWYORK BASEL Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-4032-7 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright # 2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA To my father and the memory of my mother Preface It has been about 80 years since James B. Sumner first crystallized urease to suggest the discrete structure of proteins and J. D. Bernal and Dorothy M. Crawfoot (later Hodgkin) demonstrated that protein crystals of pepsin were sufficiently ordered to diffract X-rays. In this time, protein structure has been transformed from a topic of speculation and monumental experimental challenge to a field with the aspirations and the technological capacity for enumerating the full diversity of protein folds in the biosphere. Throughout its development, the field has been guided by a single enduring principle—that to understand a protein’s structure is to begin to understand its function in molecular detail. Structural studies have indeed discovered much about proteins and their functions. They have revealed the secondary structural elements and a shared hierarchy of structural elements common to all proteins as well as the physicochemical basis of their thermodynamic stability. The framework for describing the catalytic mechanisms of enzymes derives from structural studies as do insights linking structural mutability to biological function. Structure has been used to show how the interactions of proteins with DNA and other macromolecules can regulate processes in biological development and differentiation. Large assemblies of proteins performing a broad spectrum of biological roles outside the cell, within the membrane, and inside the cell can only be understood adequately in the context of the descriptions provided by structural analysis. v vi Preface This volume is intended as a reference for the researcher with a basic knowledge of protein structure who would like to understand more about determining, analy