A team of scientists at The Scripps Research Institute and the University of Virginia has determined1 the structure of the protein package that delivers the genetic2 material of the human immunodeficiency virus (HIV) to human cells. The work is the culmination3(顶点,高潮) of studies carried out over the last decade looking at different portions of the cone4-shaped container, or the capsid(衣壳) . The final piece of the puzzle, described in an article published in Nature on January 20, 2011, details the structure of the two ends of the cone(圆锥体) .
"This paper is a real milestone5 for research from our group," says the study's senior author Mark Yeager, M.D., Ph.D., a Scripps Research professor and staff cardiologist(心脏病学家) and chair of the Molecular6 Physiology7 and Biological Physics Department at The University of Virginia School of Medicine.
A detailed8 description of the complete HIV capsid will provide a roadmap for developing drugs that can disrupt its formation and thus prevent infection by HIV.
Assembling the Package
HIV binds9 to receptors on human cells and then delivers the capsid inside them. Once inside a cell, the capsid comes apart, releasing its precious cargo—the virus's genetic material.
HIV then sabotages10(妨害,破坏) the cell machinery11 to make many copies of its genes12 and proteins. As new viruses are made, the genetic material is packaged into spherical13(球形的) immature14 capsids that HIV uses to escape from the infected cell. But before these newly released viruses can infect other cells, the immature capsid undergoes a dramatic rearrangement to form the mature, cone-shaped shell.
If formation of the mature capsid is disrupted, the virus is no longer infectious. Thus, new drugs targeting capsid formation could provide valuable additions to the arsenal15 of existing drugs against HIV.
A "Floppy16" Bridge
To develop drugs that disrupt capsid formation, however, scientists first need to know precisely17 how it is formed.
One technology researchers use to obtain detailed structures of biological molecules19 is X-ray crystallography(结晶学) . This technique requires growing crystals of a molecule18 and then bombarding the crystals with X-rays to determine the positions of all the atoms.
But unlike the cone-shaped capsids of other viruses, such as the poliovirus(小儿麻痹病毒) , which have a rigid20, symmetrical structure that obediently(顺从地) assembles into crystals, the HIV capsid is flexible and can adopt slightly different shapes.
Part of the reason for this flexibility21 is the protein that makes up the HIV capsid, the CA protein, consists of two ends held together by a "floppy" bridge.
In the capsid, each CA protein joins hands with other CA proteins, forming groups of five or six proteins. The main body of the capsid contains about 250 of the six-fold units or hexamers(六聚物) . Each end of the cone is then closed off by either five or seven smaller five-fold units or pentamers(五节聚化物) .
"It is impossible to grow crystals of the entire HIV capsid," says Yeager. As a result, his team used a "divide and conquer approach."
Divide and Conquer
Working with husband-and-wife team Owen Pornillos and Barbie Ganser-Pornillos, investigators22 in his lab, Yeager partitioned(划分,分隔) the HIV capsid into smaller components23, then determined their respective structures.
Yeager's group started by focusing on the structure of the CA hexamer. A breakthrough came in a 2007, when the group viewed the CA hexamers with a powerful electron microscope. Guided by information from that structure, in 2009 the team managed to trick the CA hexamers into forming crystals. The researchers were then able to determine the particles' structures at 2-Angstrom resolution (one Angstrom equals one ten-billionth of a meter).
Having cracked the atomic structure of the hexamer, the investigators turned their attention to the more elusive24 pentamers.