Determining the 3D Structure of HIV-1 Protease (2000)

In his News article “When Pharma merges, R&D is the dowry” (special issue on Drug Discovery, 17 Mar., p. [1952][1]), Bruce Agnew writes that “Merck researchers were the first to determine the three-dimensional structure of the HIV-1 protease enzyme in 1989,” and Roger Perlmutter is quoted as saying, “we published that structure so that everybody else could work on it, too.” However, these statements do not accurately reflect the course of events.

The human immunodeficiency virus- type 1 (HIV-1) protease structure determined crystallographically by Merck researchers using recombinantly expressed HIV-1 protease was published in Nature in early 1989 ([1][2]). This structure was of the unliganded (empty active site) enzyme and was seriously flawed because the low resolution of the data led to an incorrect tracing of the polypeptide chain at the dimer interface. In any event, only the coordinates of the carbon alpha atoms of the main chain were deposited with the Protein Data Bank (PDB). Such limited data for the unliganded enzyme were of little, if any, use to researchers undertaking structure-based drug design.

The first complete and correct structure of the HIV-1 protease was determined crystallographically at the National Cancer Institute (NCI) using enzyme prepared by total chemical synthesis in Kent's laboratory at the California Institute of Technology, and the structure was published in August 1989 ([2][3]). The more important structure of an HIV-1 protease-ligand complex was also determined at NCI, again using enzyme prepared by total chemical synthesis in Kent's laboratory at Caltech with a substrate-derived inhibitor prepared by Marshall's laboratory at Washington University at St. Louis. That structure was published in December 1989 ([3][4]). These structures of the synthetic enzyme were of high resolution and of good quality, providing an appropriate target for structure-based drug design. The full coordinates for both structures were immediately deposited in the PDB and were made freely available to researchers.

1. [↵][5]1. M. A. Navia 2. et al.
 , Nature 337, 615 (1989).
 [OpenUrl][6][CrossRef][7][PubMed][8]

2. [↵][9]1. A. Wlodawer 2. et al.
 , Science 245, 616 (1989).
 [OpenUrl][10][Abstract/FREE Full Text][11]

3. [↵][12]1. M. Miller 2. et al.
 , Science 246, 1149 (1989).
 [OpenUrl][13][Abstract/FREE Full Text][14]

# Response {#article-title-2}

As Kent, Marshall, and Wlodawer make plain, numerous groups (including their own) made contributions to the determination of the structure of the HIV-1 protease. There appear to be no serious issues of contention between us. Merck Research Laboratories made public a structural analysis of the HIV-1 protease and deposited the data in the PDB in early 1989. The structure was not “seriously flawed,” although we readily acknowledge that it was incomplete. It provided the best, and at the time the only, representation of the structure of the HIV-1 protease. Resolution of the alpha chain backbone was a fundamental first step.

Crystallographic analysis is typically iterative, and subsequent work by Kent, Marshall, and Wlodawer clearly provided substantive and more detailed information. The important point, as I indicated in Agnew's article, is that the initial publication of structural data by Navia et al. accelerated the development of protease inhibitors by several pharmaceutical companies, to the general benefit of patients suffering from HIV infection.

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