Substrate shape determines specificity of recognition for HIV-1 protease: Analysis of crystal structures of six substrate complexes
Substrate shape determines specificity of recognition for HIV-1 protease: Analysis of crystal structures of six substrate complexes
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DOI：
10.1016/s0969-2126(02)00720-7
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发表时间：
2002-03-01
期刊：
影响因子：
5.7
通讯作者：
Schiffer, CA
中科院分区：
文献类型：
--
作者：
Prabu-Jeyabalan, M;Nalivaika, E;Schiffer, CA
同型二聚体HIV-1蛋白酶是一些最有效的抗病毒艾滋病治疗的靶标，因为它通过切割Gag和Pol多蛋白中的十个不对称和非同源序列来促进病毒成熟。由于这种酶的特异性不容易仅从这些切割位点的序列中确定，因此我们用六种与天然底物切割位点相对应的肽解算了HIV-1蛋白酶的失活变体（D25N）的复合物的晶体结构。当蛋白酶与其底物结合并掩埋近1000埃(2)的表面积时，蛋白酶的对称性被打破，但大多数内部氢键和水是守恒的。然而，底物侧链氢键不保守。HIV-1蛋白酶的特异性似乎是由不对称的形状而不是特定的氨基酸序列决定的。
The homodimeric HIV-1 protease is the target of some of the most effective antiviral AIDS therapy, as it facilitates viral maturation by cleaving ten asymmetric and nonhomologous sequences in the Gag and Pol poly-proteins. Since the specificity of this enzyme is not easily determined from the sequences of these cleavage sites alone, we solved the crystal structures of complexes of an inactive variant (D25N) of HIV-1 protease with six peptides that correspond to the natural substrate cleavage sites. When the protease binds to its substrate and buries nearly 1000 Angstrom(2) of surface area, the symmetry of the protease is broken, yet most internal hydrogen bonds and waters are conserved. However, no substrate side chain hydrogen bond is conserved. Specificity of HIV-1 protease appears to be determined by an asymmetric shape rather than a particular amino acid sequence.