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26 NATURE | VOL 399 | 6 MAY 1999 | www.nature.com

A founding father ofstructural biologyNineteen sixty was the spring of hope forprotein crystallography. Thedetermination of the structures ofmyoglobin at 2-Å resolution by JohnKendrew and of haemoglobin at 5.5 Å byMax Perutz had shown how structuralstudies could yield biological information.Yet, for several years, no new proteinstructures were solved and anxiety set in.Maybe the globins had been flukes.

David Phillips’s structuredetermination of lysozyme in 1965completely changed that view. This workfirst showed the power of proteincrystallography to explain biologicalfunction in terms of physics and chemistry.It changed forever the way that enzymesare studied and was the start of theexplosion in the number of proteinstructures being solved.

Following a war-time undergraduatedegree in physics, mathematics andelectrical engineering at Cardiff University,and subsequent appointments in Cardiffand Canada, Phillips took a post-doctoralposition at the Royal Institution, London,in 1956. Sir Lawrence Bragg was directorand fostered a spirit of independence andinitiative there. Realizing that automatingthe collection of X-ray diffraction data wasa prime objective for studies of largeprotein molecules, one of Phillips’s firsttasks was to collaborate in the design andconstruction of an automateddiffractometer, an analogue device basedon a mechanical model of the diffractionlattice. With this instrument he and histeam were able to obtain highly accuratedata which, in turn, led to precisestructures (including that of myoglobin at1.4-Å resolution, an astonishing precisionfor that era).

The solution of the X-ray structure oflysozyme was based on meticulous

attention to theprecision of the X-ray diffraction dataand on the quality

of the phasesproduced by the

technique ofmultiple

isomorphousreplacement

coupled withanomalousscattering

measurements. The structure showed thecomplete path of the polypeptide chain(129 amino-acid residues) folded into botha-helices, as seen in myoglobin, and b-sheet, a structure that had been predictedby Linus Pauling but not hitherto observedin three dimensions.

Lysozyme has antibacterial activity,which was then known to be due to itsability to hydrolyse the polysaccharidecomponent of the bacterial cell wall. Evenin 1962 Phillips had been thinking aboutthe catalytic mechanism, and suggestedthat, as a graduate project, one of us(Louise Johnson) should pursue bindingstudies on inhibitor molecules. By early1966 these experiments had led to adetailed interpretation of lysozyme incomplex with an inhibitor, tri-N-acetylchitotriose, and an understanding ofthe key elements by which lysozymerecognizes sugars. The next step was towork out precisely how lysozymerecognizes its hexasaccharide substrate inthe bacterial cell wall. By molecular modelbuilding, and bringing all the availablebiochemical evidence to bear, Phillipsproduced a proposal for the way in which asubstrate must bind — and, after furtherintense thought and insights from CharlesVernon, for lysozyme’s catalyticmechanism.

Here was the first structuralexplanation of how an enzyme speeds up achemical reaction. The proposalscontained suggestions for essentially everystructural contribution to the catalyticpower of enzymes that has since beendetected — proximity, ground-statedistortion, alteration of catalytic-grouppK a by the unique environment of theenzyme, general acid–base catalysis, andtransition-state stabilization byelectrostatic and hydrogen-bondinginteractions. The extrapolation frominhibitor binding to substrate binding wasa remarkable feat of deductive reasoning. Itwas achieved in a mere three days — threedays which Phillips described as the mostrewarding he had ever spent.

In 1966, he was appointed professor ofmolecular biophysics at Oxford University,and fresh achievements followed. Mostnotably, with his graduate students hesolved the structure of triose phosphateisomerase (TIM). This was the firstexample of an eight-fold a–b-barrelprotein. David was too modest to call it a‘Phillips fold’ but he took quiet pridewhenever a new TIM-barrel (as it is nowknown) structure was announced. Thenumber is now in the hundreds.

From about the mid-1970s Phillipsbegan his second career, in science policyand administration. Scientific research, hebelieved, must be organized so that“Combined with the provision of thenecessary infrastructure, it can releaseindividual scientists to display their critically important gifts of spontaneityand originality”. These were his goalswhen, from 1983 to 1993, he was chairmanof the Advisory Board for the ResearchCouncils (ABRC), the then intermediarybody between government and theresearch councils.

His time at ABRC was not withoutcontroversy. On the one hand he had todeal with the demands for funding fromscientists faced with the growth ofscientific opportunities, the need forincreasingly complex apparatus andfacilities, and the growing importance ofinterdisciplinary research. On the otherhand he fought to persuade government todeliver more money while recognizing thenecessarily limited resources and pressuresfor concentrating them. He won therespect of both sides, emphasizing thatonly the best science should be funded,although some of his views on prioritieswere not generally appreciated at the time.The Member of Parliament Tam Dalyellhas recounted that politicians were muchin awe of him: one minister confided, “Iread my brief three times before Phillipsenters my office”.

David Phillips was appointed a life peerin 1994. He chose to keep his surname forthe title (“Otherwise one disappearsbehind a different name and nobody quiteknows who you are”); but, because therehad been a Lord Phillips before, he becameLord Phillips of Ellesmere, after hisbirthplace, a small town in Shropshireclose to the Welsh border.

Even when cancer had him deep in itsgrip, David remained at work and hecompleted a manuscript, “How thelysozyme molecule was actually solved”,just nine days before his death on 23February of this year. As Conan Doyle hasWatson say in The Final Problem: “Thiswas one of the best and wisest men we shallever know”. He was a man of remarkablewarmth and sensitivity — a true friend inthe best sense of the word.Louise N. Johnson and Gregory A. Petsko

Louise N. Johnson is in the Laboratory ofMolecular Biophysics, University of Oxford,Oxford OX1 3QU, UK.e-mail: louise@biop.ox.ac.ukGregory A. Petsko is at the Rosenstiel BasicMedical Sciences Research Center, BrandeisUniversity, 415 South Street, Waltham,Massachusetts 01254-9110, USA.e-mail: petsko@binah.cc.brandeis.edu

Obituary

David Phillips (1924—99)

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