人免疫缺陷病毒（HIV）的Tat蛋白很多年來(lái)一直是結(jié)構(gòu)研究的一個(gè)目標(biāo),，人們期望由此找到可能的治療干預(yù)方法,。Tat在感染初期具有活性，“劫持”宿主的正轉(zhuǎn)錄伸長(zhǎng)因子P-TEFb,。后者對(duì)于一個(gè)宿主蛋白來(lái)說(shuō)是不尋常的,，因此也是一個(gè)潛在的藥物作用目標(biāo)。
Tahirov等人報(bào)告了HIV Tat在與P-TEFb所形成的復(fù)合物中的第一個(gè)晶體結(jié)構(gòu),。這一2.1-A分辨率的晶體結(jié)構(gòu)顯示,，盡管Tat 和 P-TEFb之間的互動(dòng)界面很大，但Tat的結(jié)合會(huì)改變P-TEFb的結(jié)構(gòu)。這一發(fā)現(xiàn)為開(kāi)發(fā)只阻斷被病毒所利用的那種P-TEFb形式的抑制劑指出了可能的機(jī)會(huì),。(生物谷Bioon.com)
生物谷推薦原文出處：
Nature doi:10.1038/nature09131
Crystal structure of HIV-1 Tat complexed with human P-TEFb
Tahir H. Tahirov1, Nigar D. Babayeva1, Katayoun Varzavand2, Jeffrey J. Cooper2, Stanley C. Sedore2 & David H. Price2
1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA
2 Biochemistry Department, University of Iowa, Iowa City, Iowa 52242, USA
Regulation of the expression of the human immunodeficiency virus (HIV) genome is accomplished in large part by controlling transcription elongation. The viral protein Tat hijacks the host cell’s RNA polymerase II elongation control machinery through interaction with the positive transcription elongation factor, P-TEFb, and directs the factor to promote productive elongation of HIV mRNA. Here we describe the crystal structure of the Tat·P-TEFb complex containing HIV-1 Tat, human Cdk9 (also known as CDK9), and human cyclin T1 (also known as CCNT1). Tat adopts a structure complementary to the surface of P-TEFb and makes extensive contacts, mainly with the cyclin T1 subunit of P-TEFb, but also with the T-loop of the Cdk9 subunit. The structure provides a plausible explanation for the tolerance of Tat to sequence variations at certain sites. Importantly, Tat induces significant conformational changes in P-TEFb. This finding lays a foundation for the design of compounds that would specifically inhibit the Tat·P-TEFb complex and block HIV replication.
