Protein Science, Vol 1, Issue 8 1061-1072, Copyright © 1992 by Cold Spring Harbor Laboratory Press

ARTICLE

Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: Comparisons with molecular modeling

N. THANKI, JKM. RAO, S. I. FOUNDLING, W. J. HOWE, J. B. MOON, J. O. HUI, A. G. TOMASSELLI, R. L. HEINRIKSON, S. THAISRIVONGS and A. WLODAWER
Macromolecular Structure Laboratory, NCI-Frederick Cancer Research and Development Center, ABL-Basic Research Program, Frederick, Maryland 21702

The structure of a crystal complex of recombinant human immunodeficiency virus type 1 (HIV-1) protease with a peptide-mimetic inhibitor containing a dihydroxyethylene isostere insert replacing the scissile bond has been determined. The inhibitor is Noa-His-Hch{psi}[CH(OH)CH(OH)]Vam-Ile-Amp (U-75875), and its K(i) for inhibition of the HIV-1 protease is <1.0 nM (Noa = 1-naphthoxyacetyl, Hch = a hydroxy-modified form of cyclohexylalanine, Vam = a hydroxy-modified form of valine, Amp = 2-pyridylmethylamine). The structure of the complex has been refined to a crystallographic R factor of 0.169 at 2.0 A resolution by using restrained least-squares procedures. Root mean square deviations from ideality are 0.02 A and 2.4{deg}, for bond lengths and angles, respectively. The bound inhibitor diastereomer has the R configurations at both of the hydroxyl chiral carbon atoms. One of the diol hydroxyl groups is positioned such that it forms hydrogen bonds with both the active site aspartates, whereas the other interacts with only one of them. Comparison of this X-ray structure with a model-built structure of the inhibitor, published earlier, reveals similar positioning of the backbone atoms and of the side-chain atoms in the P2-P2' region, where the interaction with the protein is strongest. However, the X-ray structure and the model differ considerably in the location of the P3 and P3' end groups, and also in the positioning of the second of the two central hydroxyl groups. Reconstruction of the central portion of the model revealed the source of the hydroxyl discrepancy, which, when corrected, provided a P1-P1' geometry very close to that seen in the X-ray structure.
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