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Date: Thursay, July 11, 1996 FOR IMMEDIATE RELEASE Contact: Greg Folkers(301)402-1663 (firstname.lastname@example.org)
The protein, called the p24 capsid protein, assembles with identical proteins to form the cone-shaped structure that encloses the genetic material of HIV in a mature virus particle. In addition to its structural function, scientists speculate that the p24 capsid protein plays other important roles in the HIV life cycle.
Michael F. Summers, Ph.D., professor of biochemistry at the University of Maryland Baltimore County (UMBC), and his colleagues at UMBC and the University of Utah report their findings in the July 12 Science. Dr. Summers also will participate in a press conference on the UMBC campus on Thursday, July 11 at 2:00 p.m.
"This important new information on the structure of the HIV p24 capsid protein suggests potential new targets for drug development, and provides new insights into the process of HIV replication," says Jack Killen, M.D., director of the NIAID Division of AIDS. "This work is especially impressive because Dr. Summers' students -- undergraduates as well as graduate students and post-doctoral fellows -- have played pivotal roles in his cutting-edge research."
Previously, Dr. Summers and his team solved the structure of two other HIV structural proteins: the p7 nucleocapsid, a protein found inside the viral core; and the p17 matrix protein, found between the core and the viral membrane.
"The record of the UMBC group has been extraordinary," says Opendra Sharma, Ph.D., health scientist administrator in NIAID's Division of AIDS and the NIAID program officer for the UMBC grant. "Over the course of five years, they have provided three pieces of a remarkably difficult puzzle."
In their research, Dr. Summers and his colleagues used a technique called nuclear magnetic resonance (NMR) spectroscopy to determine in fine detail the structure of two-thirds of the p24 capsid protein. Using NMR, researchers can map the positions of hydrogen atoms in a molecule and the kinds of atoms that surround them.
Scientists have used NMR for the past decade to study proteins that do not form crystals, and therefore are not amenable to x-ray crystallography. NMR allows researchers to observe proteins in their natural state: in solution, where they are free to move.
However, the procedure is useful for only small molecules, and the p24 capsid protein is a large molecule that aggregates with other similar molecules. Therefore, the UMBC researchers initially were unsuccessful in their attempts to study the protein's structure with NMR.
"Picture the core of HIV as an eggshell composed of 2000 identical copies of the p24 capsid protein," says Dr. Summers. "Each piece of the eggshell is designed to aggregate with the others, and when we put these proteins in solution, they stuck together, becoming too large for us to study by our methods."
"Our big breakthrough came about a year ago when we figured out how to use enzymes to cut off the third of the molecule responsible for aggregation, which left us with a section of the molecule, called the amino-terminal core domain, that we could study."
Dr. Summers' collaborator at the University of Utah, Wesley I. Sundquist, Ph.D., had initially provided the UMBC group with large quantities of native p24 capsid protein, which he produced in E. coli bacteria using a special genetic engineering technique. For the current study, Dr. Sundquist and his group adapted their technique to produce large quantities of the amino-terminal core domain of the p24 capsid protein, without the part of the molecule responsible for aggregation.
The UMBC researchers found the structure of the p24 capsid protein to be unlike any other protein previously described. The amino-terminal domain has seven corkscrew-shaped "alpha-helices", two regions called "beta-hairpins," and a single, exposed loop.
The exposed loop may be of particular importance, says Dr. Summers, because it contains an amino acid -- Pro90 -- that binds a protein called cyclophilin A that HIV takes with it when it buds from a cell. The binding of cyclophilin A by Pro90 appears necessary for a viral particle to be infectious. If Pro90 is present in an abnormal form,
HIV particles are not infectious, even though they appear normal. Researchers have previously hypothesized that the binding of cyclophilin A to the p24 capsid protein changes the conformation of the protein, thereby enabling the virus to release its genetic contents into a target cell.
In their experiments, Dr. Summers and his group observed that Pro90 exists in two separate conformations.
"One of these conformations may be necessary for the p24 capsid proteins to assemble to form the viral core, and the other conformation is necessary for the core to disassemble," he says. "Pro90 may serve as a molecular switch for capsid assembly or disassembly, with cyclophilin A either 'flipping the switch' or locking it into a particular position."
"We now have a detailed picture of what the cyclophilin A binding site of the HIV p24 capsid protein looks like," Dr. Summers adds. "It may now be possible for experts in drug design to take this structure and develop a drug that would bind to the site and thereby block cyclophilin A binding, and perhaps HIV infectivity."
"The capsid proteins of other viruses have been successfully targeted in drug design," he notes. Dr. Summers' collaborators include Rossitza K. Gitti, Ph.D., Brian M. Lee and Jill Walker, of UMBC; and Sanghee Yoo and Wesley I. Sundquist, Ph.D., of the University of Utah.
In addition to funding from NIAID, Dr. Summers and his team received support from the National Institute of General Medical Sciences (NIGMS) and the Howard Hughes Medical Institute, where Dr. Summers is an associate investigator.
NIAID and NIGMS are components of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
NIAID press releases, fact sheets and other materials are available on the internet via the NIAID home page. The address is www.niaid.nih.gov.