This meeting is dedicated to the memory of Paul B. Sigler, who passed away in the early morning of January 11, 2000. While 65 years old, an age when many might be relaxing on past successes, Paul was in mid-course of achieving greater and greater heights of structural and chemical understanding of basic biological systems of transcription, signal transduction, interfacial catalysis, and chaperonin-mediated protein folding. As a father of five grown children, he was also savoring, with his wife Jo, the arrival and maturation of 7 grandchildren living both in the U.S. and in Jerusalem. Over the years Paul developed long-lasting relationships with many colleagues and friends, attracted by his personality and his scientific charisma and leadership -- we will all miss him.

Enthusiasm and scientific charisma are probably the terms that best describe this most remarkable man. His excitement and raw energy, and pure scientific intuition, coupled with an amazing grasp of virtually any biological problem under study, from the level of the intact animal to atomic resolution, made him one of the most sought-out people one could ever imagine. The breadth of Paul's work is truly legendary. His earlier work at MRC/LMB and the University of Chicago focused on structural studies of chymotrypsin, initiator tRNA, and phospholipases. This was followed by the trp repressor project , which brought a major surprise: the crystal structure of the repressor/operator complex showed that the DNA sequence seemed to be recognized indirectly, and that the specific interactions were in part water-mediated. These early studies were expanded at Yale on other protein/DNA projects. As a result, Paul's lab made a major impact on our understanding of transcriptional regulation in eukaryota. The transcription work also included more complex systems: TBP/TATA-box complex, TFIIA/TBP/TATA, TBP/TFB/promoter, glucocorticoid receptor bound to DNA, RXR-TR bound to response element, NF-ºB bound to a ºB site, BPV E2 DBD bound to its target. These studies also directed Paul’s attention to signal transduction: G_±-transducin complexed with GTP³S, then with GDP, then the whole heterotrimeric G, visual arrestin, fosducin complexed with G, pleckstrin homology domain. One of the biggest challenges to Paul’s scientific curiosity was the chaperonin system, a large and complex molecular machine, that presented an unparalleled level of difficulty. The chaperonin work included: GroEL, GroEL-ATP³S, GroEL-GroES-ADP₇ and GroEL-peptide. The case of GroEL is a stunning example. In the unliganded structure, the open GroEL rings expose a hydrophobic cavity surface that captures non-native proteins. Upon binding of ATP and GroES, however, there are large rigid body motions of the domain bearing this surface, elevating it and twisting it 90° , so that the hydrophobic surface is removed and replaced by a hydrophilic one. This explains the functional results of GroES and ATP binding, which ejects polypeptide off the binding sites into a sequestered cavity, where the protein folds.

These crystallographic studies were always complemented by biochemical and functional experiments, "to understand how these molecules work on the molecular level." Paul was constantly trying to describe the biological systems at the most detailed molecular and chemical levels that were possible. By doing that, he was fearlessly fighting the "black boxes" approach in science and in life. He continuously demanded clear thought and understanding from his students and research associates, reflecting his strong desire to educate young scientists to seek scientific authenticity with a deep understanding of the methods, approaches, and their limitations.

We are left to plunge ahead as he would have wanted us to, pursuing structural and functional understandings of larger and more complex assemblies, without fear, with the confidence that he gave all of us that these are challenges that can be tackled successfully. Those of us who worked with him will continue to hear those admonishments clearly.