Structural Biology Research Center (SBRC)
Science Advisory Committee
Summary
February 14, 2020
Advisor:Alexander Wlodawer, Ph.D.
Chief, Macromolecular Crystallography Laboratory,
National Cancer Institute (NCI),
Frederick, MD, USA

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Institute of Materials Structure Science (IMSS)High Energy Accelerator Research Organization (KEK)Based on the presentations by staff members of SBRC, as well as on
the written activity report covering the years 2014-2019, I would like toanswer the following questions raised during the first meeting of theKEK-SAC.
(https://www.kek.jp/ja/About/OrganizationOverview/Assessment/Roadmap/1st_KEKSAC.pdf)

1. There is clear scientific excellence across the materials science andstructural biology portfolio, as well as strong examples of industrialrelevance. At the next meeting, we would like KEK to clarify where
believes it holds, or could hold, a leadership position in materials
science or structural biology.
It is my understanding that SBRC is principally responsible for the structural biology portfolio ofKEK. SBRC plays a double role – it is responsible for the management of the structural biology
pipeline for the university-based scientific community, as well as conducting its own research
projects. With the scientific staff of ~40, supported by 5 administrators, the SBRC is tasked with
providing access to the state-of-the-art protein expression and purification facility, operation offive Photon Factory (PF) synchrotron beamlines devoted to protein crystallography (MX), as
well as two beamlines for biological small-angle scattering (SAXS). Additionally, for the last twoyears SBRC has been operating a Talos Arctica cryo-electron microscope.

2Answers to KEK-SAC (cont.):
Historically PF has been the first MX facility in Japan and one of the first ones anywhere in theworld. Although by now not among the most powerful X-ray sources, it is still competitive withthe best synchrotrons, to a large extent due to its high level of automation, allowing operation
with comparatively very small staff. Its macromolecular crystallization facility is unique inacademic environment, since it is completely automated, allowing setting up the experiments
and monitoring their outcome in a manner that requires only minimal staffing. Some of thebeamline facilities are unique in their capabilities. For example, beamline BL-1A is optimized forcollecting data using long-wavelength radiation that maximizes the anomalous scattering of thesulfur atoms present in native proteins. The samples and the detector are enclosed in a heliumfilled chamber, thus avoiding air scattering. This uncommon facility has been successfully used
to determine a number of de novo protein structures without the need to derivatize the samples
with heavy atoms. Another unique facility available in SBRC is the anaerobic chamber for
crystallization of proteins while excluding oxygen.
The facilities operated by SBRC are extensively utilized by about 200 groups of academic andindustrial scientists from a number of different institutions, as documented by the publication
record that varies between ~150 and ~175 publications per year. Additionally, about 20publications are published each year by the SBRC staff, a significant fraction of which are inleading journals. About 300 sets of coordinates and structure factors are deposited each year in
the Protein Data Bank. These are clear indications of the value of the resources provided by
SBRC.

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Answers to KEK-SAC (cont.):
2. The KEK-SAC would also like to hear about KEK’s current andfuture leadership roles in structural biology.
It is very clear that SBRC has been playing a leadership role in Japan by enabling access tohigh-quality instrumentation for academic researchers, as well as by conducting very highquality in-house projects. The latter activities are very important, since they set a very highstandard of performance for the facility users and for scientific collaborators. Although attachedto the Photon Factory, SBRC provides leadership not only in synchrotron-related aspects ofstructural biology, but also in biochemistry and imaging. Of particular importance is the recent
addition of a cryo-EM instrument. However, the currently available 200 kV microscope is not
sufficient to maintain the leadership role for the future and since cryo-EM is rapidly becoming
the principal technique in studies of macromolecular complexes, it is absolutely necessary toexpand the range of available instrumentation, preferably by adding both a 300 kV microscope,
as well as a smaller microscope for sample evaluation. It is also clear that in the long range it
will be necessary to upgrade the flux of the synchrotron X-ray source and continue upgrading
the beamline instrumentation if the future leadership roles are to be maintained.

4Answers to specific questions:
1. How does SBRC-SAC evaluate the leadership of SBRC in the field ofstructural biology? Has SBRC been a core academic research hub?
It is clear that SBRC has been a leader in the field of structural biology. Staff of SBRC has been
involved in a number of high-importance scientific investigations, mostly through theirinvolvement in national projects, first PDIS and then BINDS. Of particular interest is the projectof investigating GTP metabolism that resulted in identification of a cellular GTP sensor.
Glycobiology is another very interesting area of investigations, with extensive research on
glycosyltransferases and lectins. Research on infective diseases resulted in structural studies
of multidrug resistance transporters and H. pylori effector proteins. Studies of transcription
initiation factors and redox enzymes have been also conducted on very high level. There is no
doubt in my mind that SBRC is a go-to laboratory for cutting edge collaborative projects.

2. Have SBRC users in addition to in-house scientists been makingoutstanding contributions to structural biology and interdisciplinaryscientific fields?
The users of both the MX and BioSAXS instruments have been very successful in obtaining highquality results and in publishing them. Examples include structural investigations of Toll- like receptors,
LHC-II, autophagy related protein complexes, and onco-protein from Helicobacter pylori, amongothers. Structural analysis of VDR that combined the use of methods such as MX, BioSAXS, andmolecular dynamics showed the power of merging results obtained by complementary techniques.

5Answers to specific questions (cont.):
3. Does SBRC play a role of an international academic research center?
SBRC has been engaged in a number of successful international collaborative efforts on
projects in the area of infectious disease, studies of the process of gene transcription, as well as
GTP metabolism. Based on an agreement with the Swiss Light Source (SLS), several of theirscientists have been visiting PF every year, principally to use the unique capabilities of thebeamline BL-1A that allow direct phasing based on anomalous scattering of sulfur atoms. Otherforeign users have been utilizing the crystal-shaping instrument (moved from Spring-8). Theseprojects provided a basis of a workshop during the 69th annual meeting of the American
Crystallographic Association that took place in Covington, KY in 2019. SBRC staff were able touse the facilities of SLS during summer periods when no MX beamlines are operational in
Japan. Foreign visitors have been coming to SBRC, some for extended period of time, andSBRC staff has travelled abroad and presented their results in international conferences.

6Answers to specific questions (cont.):
4. Does SBRC provide appropriate support for researchers/visitors fromabroad?
Foreign visitors to SBRC need English-language support from the scientific and administrativestaff. Whereas it is assumed that the scientists and engineers should be reasonably fluent in thelanguage, this might not always be true for the administrative staff. However, as I found myself,
administrators were able to make all the arrangements for my travel and stay in Tsukuba without
having to involve the scientific staff. I assume that the same acceptable level of support isavailable to all foreign visitors to SBRC. Thus, in my opinion, the facility makes it easy for theforeigners to obtain necessary information and guidance.

7Answers to specific questions (cont.):
5. How does SBRC-SAC evaluate the effort of expanding the research
fields by SBRC? Does SBRC create networks for scientific collaborationand discuss reorganization with different research organizations orfields?
Considering the relatively small size of the staff of SBRC it is difficult to recommend a significant
expansion of the covered areas of interest. The existing extensive networks already prove that
SBRC is very helpful to the scientific community, but further expansion of projects may dilute theefforts due to the lack of resources, mainly human.

6. How does SBRC-SAC evaluate contributions to education in
Academia?
Presentations at national and international meetings are very helpful in making the scientificcommunity, including students and postdocs, aware of the results obtained by SBRC staff. A
large number of workshops and seminars also contribute to the success of educational efforts.

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Answers to specific questions (cont.):
7. How does SBRC-SAC evaluate the PR activities?
The presence of many visitors, including foreign, is very helpful in making SBRC better known
in the scientific community. The PR activities seem to be adequate.

8. How does the SBRC-SAC evaluate the present status of the SBRC?
SBRC is a vibrant organization with well thought-through research program. It provides very
important service to the structural biology community in Japan. Some of the services offered by
SBRC are unique and important.

9. How does the SBRC-SAC evaluate research projects in SBRC? Are
these research outputs adequate?
As already mentioned above, the research projects conducted in SBRC are generally wellchosen, important, and carried to completion. A number of manuscripts published in highimpact journals provide an evidence of the quality of science. The research output is certainly
adequate considering the relatively small size of the scientific staff and the need to share thehuman resources between service and in-house research.

9Answers to specific questions (cont.):
10. How does the SBRC-SAC evaluate the recent developments offacilities in SBRC?
The level of automation for protein expression, crystallization, and data collection is quite
impressive. Of course, there is a limitation of what can be accomplished on the beamlines dueto the fact that the synchrotron itself is rather old and SBRC has to live with the photon fluxesthat they cannot control. Addition of more cryo-EM instrumentation would be very helpful inkeeping SBRC at the forefront of modern structural biology.

11. How does the SBRC-SAC evaluate the funding situation of SBRC?
It is my understanding that the core funding of SBRC from the KEK provides only a small fraction of thetotal budget and a more stable institutional support would certainly be helpful. Since a large part of theefforts are directed to helping outside academic organizations, relying principally on grants might not bethe most efficient way to secure proper funding. Current funding does not allow hiring more staff thatcould support outside users that conduct research on the MX and SAXS beamlines – for example, asimilar organization in the United States is the Structural Biology Center/Midwest Center for StructuralGenomics at Argonne. In that case about 12 staff support only 2 beamlines, whereas SBRC operates 7beamlines with fewer than 20 support staff. Similarly, SER-CAT operates two beamlines at Argonnewith a dozen staff. Thus it appears that improvement in the funding, in particular by making it morepredictable year-to-year might be very helpful for assuring continuing future success of SBRC.

10Answers to specific questions (cont.):
12.
How ofdoes
Evaluation
SBRCthe SBRC-SAC evaluate the relationship with industries?
PAGE 5
SBRC provides services to industrial partners for a fee, and these additional funds are clearly helpful
in maintaining a healthy level of funding. With not much material provided in the reports (written ororal
it is indifficult
fordirection?
me to provide
evaluationof this subject.
13. presentations),
Is SBRC moving
the right
Are themore
futuredetailed
development
items adequate?
consider SBRC to be a mature organization that is doing very well now and that is likely to
13. Is Icontinue
SBRC
moving in the right direction? Are the future development
its high level of productivity well into the future. In the long term some of theitems developments
adequate?
will be affected by plans to upgrade the capabilities of synchrotrons and theprovision of more cryo-EM instrumentation.

I consider SBRC to be a mature organization that is doing very well now and that is likely to continue its
high level of productivity well into the future. In the long term some of the developments will be affected
I hope that you will find this evaluation to be helpful.
by plans to upgrade the capabilities of synchrotrons and the provision of more cryo-EM instrumentation.
Sincerely,

Alexander Wlodawer, Ph.D.
Chief, Macromolecular Crystallography Laboratory, NCI
Foreign Member, Polish Academy of Sciences
Fellow, American Crystallographic Association11