Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Structure of key molecule in immune system provides clues for designing drugs

28.12.2010
A team from the University of Pennsylvania School of Medicine and Utrecht University has deciphered a key step in an evolutionarily old branch of the immune response. This system, called complement, comprises a network of proteins that “complement” the work of antibodies in destroying foreign invaders. It serves as a rapid defense mechanism in most species from primitive sponges to humans.

In a study published in the December 24 issue of Science, the groups of John Lambris, PhD, the Dr. Ralph and Sally Weaver Professor of Research Medicine at Penn, and Piet Gros at Utrecht, detail the atomic structure of two key transient enzyme complexes in the human complement system.

Complement proteins mark both bacterial and dying host cells for elimination by the body's cellular cleanup services and have been implicated in at least 30 diseases, including stroke, myocardial infarction, and age-related macular degeneration. The findings, Lambris says, provide a molecular scaffold for designing novel drug therapeutics.

"Now we will be able to design specific complement inhibitors to target this complex and in that way inhibit activation of the complement cascade, because now we know which parts of the proteins are essential for activity," Lambris says.

Guided By Self-Control
The complement system is a form of "innate," or generic immunity, unlike "adaptive" immune responses, in which cellular mediators such as B and T cells learn to target specific antigens through recognition by either antibodies or cell receptors. The complement process unfolds as a complex biochemical network of molecular and cellular communication events, which result in the destruction and elimination of pathogens and damaged cells and eventual recruitment of immune cells.

The two enzyme complexes Lambris studied, called C3bB and C3bBD, drive a central step in amplifying the response by complement proteins. In that step, the complement protein C3 is enzymatically cleaved to form C3b, which binds to the surface of a target cell. C3b then binds factor B to produce C3bB. This complex, in turn, binds another enzyme, factor D (producing C3bBD), which cleaves the complex to form the active C3bBb. The major target of the active C3bBb is C3 itself, resulting in rapid amplification of the complement cascade.

To capture structural snapshots of C3bB and C3bBD, the researchers first generated mutant proteins that would stabilize the complexes in their active forms. Then, Lambris and Gros used x-ray crystallography to describe the two complexes in atomic detail. They found that, upon binding to C3b, factor B changes its shape to form an "open complex," which can then be bound by factor D. Factor D, in turn, shifts its shape in a more subtle yet no less important way: The free protein is inactive because a protein loop blocks the active site of the enzyme. Upon binding to C3bB, that loop alters its position, thereby activating factor D to cleave C3bB into the C3bBb complex.

These findings, Lambris said, provide molecular explanations for several safety features of the complement system. First, they explain why factor D is inactive on its own, but active when engaged by C3bB. They also illustrate a "double safety catch" mechanism the system uses to keep itself in check, preventing complement activation in the absence of a target.

Finally, and perhaps most importantly, they provide data that can aid the design of inhibitors against factor D, which may prove useful in the treatment of complement-associated diseases.

"Besides shedding light on a highly elegant mechanism of concerted activation and intrinsic regulation, this work also offers a detailed insight into one of the most important therapeutic targets within the complement network, which may facilitate rational drug development and could lead to novel drugs for treating complement-related diseases," Lambris says.

Co-authors include Federico Forneris, Jin Wu, and Rachel Wallace of Utrecht University, and Penn researchers Daniel Ricklin and Apostolia Tzekou.

The research was funded by the Netherlands Organization for Scientific Research and the National Institute of Allergy and Infectious Diseases and National Institute of General Medical Sciences.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise.

Penn’s School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools, and is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.

Penn Medicine’s patient care facilities include:

The Hospital of the University of Pennsylvania – the nation’s first teaching hospital, recognized as one of the nation’s top 10 hospitals by U.S. News & World Report.

Penn Presbyterian Medical Center – named one of the top 100 hospitals for cardiovascular care by Thomson Reuters for six years.

Pennsylvania Hospital – the nation’s first hospital, founded in 1751, nationally recognized for excellence in orthopaedics, obstetrics & gynecology, and psychiatry & behavioral health.

Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2009, Penn Medicine provided $733.5 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>