The Contribution of Naturally Occurring Polymorphisms in Altering the Biochemical and Structural Characteristics of HIV-1 Subtype C Protease

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• 作者：Roxana M. Coman ; Arthur H. Robbins ; Marty A. Fernandez ; C. Taylor Gilliland ; Anthony A. Sochet ; Maureen M. Goodenow ; Robert McKenna ; Ben M. Dunn
• 刊名：Biochemistry
• 出版年：2008
• 出版时间：January 15, 2008
• 年：2008
• 卷：47
• 期：2
• 页码：731 - 743
• 全文大小：499K
• 年卷期：v.47,no.2(January 15, 2008)
• ISSN：1520-4995

文摘

Fourteen subtype B and C protease variants have been engineered in an effort to study whetherthe preexistent baseline polymorphisms, by themselves or in combination with drug resistance mutations,differentially alter the biochemical and structural features of the subtype C protease when compared withthose of subtype B protease. The kinetic studies performed in this work showed that the preexistentpolymorphisms in subtype C protease, by themselves, do not provide for a greater level of resistance.Inhibition analysis with eight clinically used protease inhibitors revealed that the natural polymorphismsfound in subtype C protease, in combination with drug resistance mutations, can influence enzymaticcatalytic efficiency and inhibitor resistance. Structural analyses of the subtype C protease bound to nelfinavirand indinavir showed that these inhibitors form similar interactions with the residues in the active site ofsubtype B and C proteases. It also revealed that the naturally occurring polymorphisms could alter theposition of the outer loops of the subtype C protease, especially the 60's loop.