Press Release
Embargoed until Monday, 29 May 2006, 22:00 GMT
New potential drug target in tuberculosis
Scientists reveal structure of a key tuberculosis protein
Figure by Qingjun Ma, EMBL Hamburg
Ribbon representation of the structure of the M. tuberculosis protein LipB
with bound lipid inhibitor.
Hamburg/Berlin, 29 May 2006 – Tuberculosis remains one of the
deadliest threats to public health. Every year two million people
die of the disease, which is caused by the microorganism
Mycobacterium tuberculosis. Roughly one third of the world's
population is infected and more and more bacterial strains have
developed resistance to drugs. Researchers from the Hamburg
Outstation of the European Molecular Biology Laboratory
(EMBL) and the Max Planck Institute for Infection Biology
(MPIIB) in Berlin have now obtained a structural image of a pro-
tein that the bacterium needs for survival in human cells. This
image reveals features of the molecule that could be targeted by
new antibiotic drugs. The results appear in this week's online issue
of the Proceedings of the National Academy of Sciences (PNAS).
M. tuberculosis is dangerous because it hides and persists in the
immune cells of our bodies. “It can only persist there because of
the activity of key molecules,” says Matthias Wilmanns, Head of
EMBL Hamburg. “We are investigating the functions of tubercu-
losis proteins and determining their atomic structures, in hopes of
finding weak points and new inhibitors.”
A protein called LipB is essential for the organism because it acti-
vates cellular machines that drive the bacterium’s metabolism.
Stefan Kaufmann’s department at the MPIIB has specialised in the
Source Article
Q. Ma, M. Wilmanns et al. The Mycobacterium tuberculosis LipB enzyme functions as a cysteine/lysine dyad acyltransferase, PNAS
online, 29. Mai 2006
Contacts:
Anna-Lynn Wegener, EMBL Press Officer, Heidelberg, Germany, Tel: +49 6221 387 452, www.embl.org, wegener@embl.de
Dr Sabine Englich, MPIIB Public Relations, Berlin, Germany, Tel: +49 30 28460 142, englich@mpiib-berlin.mpg.de
biology of M. tuberculosis infection and its ability to survive in
immune cells. They discovered that LipB is highly active in
acutely infected cells, particularly in patients infected by mul-
tidrug-resistant forms of M. tuberculosis.
“In these cells we see a 70-fold increase in the production of LipB
when compared to other cells," says Stefan Kaufmann, Director at
the MPIIB. “This strongly indicates an involvement in pathogen-
esis and makes it a particularly interesting target where tradition-
al drugs have lost their efficacy.”
A structural picture of the protein - a kind of technical diagram of
its building plan - has yielded important clues about its activity.
Qingjun Ma from Wilmanns’ group purified LipB and obtained
crystals of the molecule. Using the high-energy synchrotron radi-
ation beamlines at EMBL Hamburg, on the campus of the
German Electron Synchrotron Radiation Facility (DESY), he cre-
ated an atom-by-atom map of the protein’s structure. A high-
resolution picture of the active site of LipB bound to a lipid
inhibitor helped to determine the function of the enzyme. In col-
laboration with EMBL’s Proteomics Core Facility in Heidelberg
and researchers from the University of Illinois (USA), the
Hamburg group discovered how LipB attaches specific fatty acids
onto other proteins.
“LipB is a very promising drug target,” Wilmanns says, “because it
belongs to a vital pathway. Unlike other organisms M. tuberculo-
sis has no backup mechanism that could take over LipB’s role. This
means that an inhibitor blocking its active site would shut down
key processes the bacterium needs to survive and replicate. This
would be a very effective strategy for a drug.”
The scientists will now search for compounds that can do so. At
the same time, they are continuing to look for other proteins as
drug targets. Wilmanns and his colleagues from various other
institutes are now focusing on structures of molecules that help
M. tuberculosis to persist in its dormant state and could become
drug targets.
Over the past three years, EMBL has coordinated an “M. tubercu-
losis structural proteomics” consortium, supported by the
German Ministry of Education and Research (BMBF), and pro-
duced high resolution images of more than 30 proteins.
“Structure-based drug discovery has been a big success in the
battle against many other diseases. We are now applying these
tools to tuberculosis, one of the most devastating infectious dis-
eases of mankind,” Wilmanns concludes.
About EMBL
The European Molecular Biology Laboratory is a basic research institute funded by public research monies from 19 member states
(Austria, Belgium, Croatia, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, the Netherlands, Norway, Portugal,
Spain, Sweden, Switzerland and the United Kingdom). Research at EMBL is conducted by approximately 80 independent groups cover-
ing the spectrum of molecular biology. The Laboratory has five units: the main Laboratory in Heidelberg, and Outstations in Hinxton
(the European Bioinformatics Institute), Grenoble, Hamburg, and Monterotondo near Rome. The cornerstones of EMBL’s mission are:
to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in
the member states; to develop new instruments and methods in the life sciences and to actively engage in technology transfer activities.
EMBL’s International PhD Programme has a student body of about 170. The Laboratory also sponsors an active Science and Society
programme. Visitors from the press and public are welcome.

About EMBL Hamburg

EMBL Hamburg is situated on the campus of the German Synchrotron Research Center (DESY) in Hamburg-Bahrenfeld, Germany.
DESY hosts leading facilities for synchrotron radiation (DORIS-III, in operation, PETRA-III, under construction, user operation
planned for 2009) and electron lasers (VUV-FEL, commissioned; X-FEL, planned). EMBL Hamburg operates seven experimental sta-
tions with applications in structural biology, using synchrotron radiation from the DORIS III ring. In addition, it runs a biochemistry
laboratory hosting a pipeline for sample preparation and characterisation. It also includes facilities for high cell density fermentation,
semi-automated protein purification and mass spectrometry. Start of operation of new state-of-the-art beamlines at the storage ring
PETRA-3 is planned for 2009-2010. Research at EMBL Hamburg is tightly associated with the available synchrotron experiment sta-
tions for applications in life sciences. Several projects are aimed at developing novel technologies to advance methods in structural
biology in terms of automation and user friendliness. In addition, faculty members from EMBL Hamburg lead a number of research
projects to meet great challenges in structural biology. EMBL Hamburg provides a unique research environment for advanced training
by hosting visits and offering specialised courses and workshops.

About the Max Planck Institute for Infection Biology

The Max Planck Institute for Infection Biology (www.mpiib-berlin.mpg.de) is one of Europe's centres of excellence committed to bio-
logical research in the field of infectious diseases and tuberculosis. The Institute uses multi-disciplinary approaches to infection biolo-
gy, comprising concepts and methodologies of molecular genetics, immunology, cell biology, molecular epidemiology, clinical research
and structural chemistry. It promotes the applications of its research towards paving the way for the design of rational measures of con-
trol of infectious diseases. The Institute is provided with state-of-the-art facilities, including Biological Safety Level 3 labs for tubercu-
losis wet lab and aerosol infection experiments. Support is being provided by core facilities for microarray analyses, microscopy, cyto-
fluorimetry, protein analyses, protein purification, and bioinformatics.
The research of the Department of Immunology aims at a better understanding of the biology of mycobacterial pathogens and the iden-
tification, structural and functional characterisation of mycobacterial molecules essential for intracellular survival as well as for
virulence and persistence. A major goal is the development of novel intervention measures and rational vaccine design for M. tubercu-
losis infections.

About the M. tuberculosis structural proteomics consortium

EMBL Hamburg is coordinating a joint effort by four academic partners and three industrial partners to make use of structural biolo-
gy methods for the development of new drugs against tuberculosis. Further partners of the consortium are: Prof. Stefan S.H.E.
Kaufmann, Department of Immunology Max Planck Institute for Infection Biology (Berlin); Dr. Hans Bartunik, Max Planck
Arbeitsgruppe für strukturelle Molekularbiologie (Hamburg); Prof. Hartmut Oschkinat, Forschungsinstitut für Molekulare
Pharmakologie (Berlin); Prof. Dmitrij Frishman, Technische Universität München; Dr. Markus Schade, Combinature Biopharm AG
(Berlin); Dr. Claudio Klein, MarResearch GmbH (Norderstedt); Dr. Andreas Kaps, Biomax Informatics AG (Martinsried). The consor-
tium is funded as a ProteomicsNetwork (http://www.proteomicsnetwork.de/) by the Germany Ministry of Science and Education
(BMBF).

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