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Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari; Kimura, Kaname*; Matsumura, Hiroyoshi*; et al.
Proceedings of the National Academy of Sciences of the United States of America, 106(12), p.4641 - 4646, 2009/03
Times Cited Count:114 Percentile:90.55(Multidisciplinary Sciences)To further understand the catalytic mechanism and inhibitor recognition of HIV-1 protease, we need to determine the locations of key hydrogen atoms in the catalytic aspartates Asp25 and Asp125. The structure of HIV-1 protease in complex with transition-state analog KNI-272 was determined by combined neutron crystallography at 1.9 resolution and X-ray crystallography at 1.4
resolution. The resulting structural data shows that the catalytic residue Asp25 is protonated and that Asp125 is deprotonated. The proton on Asp25 makes a hydrogen bond with the carbonyl group of the allophenylnorstatine group in KNI-272. The deprotonated Asp125 bonds to the hydroxyl proton of Apns. The results provide direct experimental evidence for proposed aspects of the catalytic mechanism of HIV-1 protease; and can therefore contribute substantially to the development of specific inhibitors for therapeutic application.
Kasugai, Atsushi; Sakamoto, Keishi; Hayashi, Kenichi*; Takahashi, Koji; Shoyama, Hiroaki*; Kajiwara, Ken*; Ikeda, Yoshitaka; Kariya, Tsuyoshi*; Mitsunaka, Yoshika*; Fujii, Tsuneyuki; et al.
JAERI-Research 2002-027, 57 Pages, 2002/11
no abstracts in English
Takahashi, Koji; Imai, Tsuyoshi; Sakamoto, Keishi; Kobayashi, Noriyuki*; Mori, Seiji*; Mori, Kensuke*; Ito, Yasuyuki*; Shoyama, Hiroaki; Kasugai, Atsushi
Fusion Engineering and Design, 56-57, p.587 - 592, 2001/10
Times Cited Count:7 Percentile:48.26(Nuclear Science & Technology)no abstracts in English
Shoyama, Hiroaki; Sakamoto, Keishi; Hayashi, Kenichi*; Kasugai, Atsushi; Tsuneoka, Masaki; Takahashi, Koji; Ikeda, Yukiharu; Kariya, Tsuyoshi*; Mitsunaka, Yoshika*; Imai, Tsuyoshi
Japanese Journal of Applied Physics, Part 2, 40(8B), p.L906 - L908, 2001/08
Times Cited Count:28 Percentile:71.54(Physics, Applied)no abstracts in English
Kasugai, Atsushi; Sakamoto, Keishi; Takahashi, Koji; Kajiwara, Ken; Shoyama, Hiroaki; Ikeda, Yukiharu; Tsuneoka, Masaki; Ikeda, Yoshitaka; Fujii, Tsuneyuki; Kariya, Tsuyoshi*; et al.
Fusion Engineering and Design, 53(1-4), p.399 - 406, 2001/01
Times Cited Count:17 Percentile:74.32(Nuclear Science & Technology)no abstracts in English
Shoyama, Hiroaki; Sakamoto, Keishi; Hayashi, Kenichi*; Kasugai, Atsushi; Takahashi, Koji; Tsuneoka, Masaki; Ikeda, Yukiharu; Kariya, Tsuyoshi*; Mitsunaka, Yoshika*; Imai, Tsuyoshi
Shingaku Giho, 100(506), p.39 - 44, 2000/12
no abstracts in English
Imai, Tsuyoshi; Sakamoto, Keishi; Kasugai, Atsushi; Tsuneoka, Masaki; Takahashi, Koji; Shoyama, Hiroaki; Ikeda, Yukiharu; Ikeda, Yoshitaka; Kajiwara, Ken; Fujii, Tsuneyuki; et al.
Heisei-12-Nendo Denki Gakkai Genshiryoku Kenkyu Shiryo (NE-00-4), p.19 - 24, 2000/09
no abstracts in English
Sakamoto, Keishi; Kasugai, Atsushi; Shoyama, Hiroaki; Hayashi, Kenichi*; Takahashi, Koji; Tsuneoka, Masaki; Ikeda, Yukiharu; Ikeda, Yoshitaka; Kajiwara, Ken; Moriyama, Shinichi; et al.
25th International Conference on Infrared and Millimeter Waves Conference Digest, p.11 - 12, 2000/00
no abstracts in English
Shoyama, Hiroaki; Kasugai, Atsushi; Sakamoto, Keishi; Takahashi, Koji; Tsuneoka, Masaki; Ikeda, Yukiharu; Kajiwara, Ken; Ikeda, Yoshitaka; Fujii, Tsuneyuki; Kariya, Tsuyoshi*; et al.
Journal of Plasma and Fusion Research SERIES, Vol.3, p.368 - 371, 2000/00
no abstracts in English
Sakamoto, Keishi; Kasugai, Atsushi; Shoyama, Hiroaki; Takahashi, Koji; Tsuneoka, Masaki; Ikeda, Yukiharu; Kajiwara, Ken; Ikeda, Yoshitaka; Kariya, Tsuyoshi*; Mitsunaka, Yoshika*; et al.
Shingaku Giho, 99(498), p.37 - 42, 1999/12
no abstracts in English
Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro*; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari*; Matsumura, Hiroyoshi*; Adachi, Hiroaki*; et al.
no journal, ,
HIV-1 protease is a dimeric aspartic protease that cleaves the nascent polyproteins of HIV-1 and plays an essential role in viral replication. To further understand the catalytic mechanism of HIV-1 protease, we have determined the crystal structure of HIV-1 protease in complex with a transition state mimetic tripeptide inhibitor, KNI-272 to 1.9 ; resolution by neutron crystallography in combination with 1.4
; resolution X-ray diffraction data. Our results indicates that the carbonyl group of allophenylnorstatine (Apns) in KNI-272 forms a significant hydrogen bond with protonated Asp 25, and the hydrogen atom from the hydroxyl group of Apns forms a remarkable hydrogen bond with the deprotonated Asp125. These results show direct evidence that Asp25 provides a proton to carbonyl group of substrate and Asp125 contributes to activate the attacking water molecule as a nucleophile.
Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari; Kimura, Kaname*; Matsumura, Hiroyoshi*; et al.
no journal, ,
HIV-1 protease is a dimeric aspartic protease that cleaves the nascent polyproteins of HIV-1 and plays an essential role in viral replication. To further understand the catalytic mechanism of HIV-1 protease, we have determined the crystal structure of HIV-1 protease in complex with a transition state mimetic tripeptide inhibitor, KNI-272 to 1.9 resolution by neutron crystallography in combination with 1.4
resolution X-ray diffraction data. Our results indicates that the carbonyl group of allophenylnorstatine in KNI-272 forms a significant hydrogen bond with protonated Asp 25, and the hydrogen atom from the hydroxyl group of Apns forms a remarkable hydrogen bond with the deprotonated Asp125. These results show direct evidence that Asp25 provides a proton to carbonyl group of substrate and Asp125 contributes to activate the attacking water molecule as a nucleophile.
Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari; Matsumura, Hiroyoshi*; Sugiyama, Shigeru*; et al.
no journal, ,
We have determined a crystal structure of HIV-1 protease by neutron crystallography. The development of HIV-1 protease inhibitors is regarded as a major success of structure-based drug design and contributes to establish highly active anti-retroviral therapy for AIDS. To further understand the catalytic mechanism of HIV-1 protease and interaction between HIV-1 protease and its inhibitor, we have determined the crystal structure of HIV-1 protease in complex with a inhibitor, KNI-272 to 2.3 resolution by neutron crystallography. Our results indicates that the carbonyl group of allophenylnorstatine (Apns) in KNI-272 forms a significant hydrogen bond with protonated Asp 25, and the hydrogen atom from the hydroxyl group of Apns forms a remarkable hydrogen bond with the deprotonated Asp125. These results show direct evidence that Asp25 provides a proton to carbonyl group of substrate and Asp125 contributes to activate the attacking water molecule as a nucleophile.
Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari; Matsumura, Hiroyoshi*; Sugiyama, Shigeru*; et al.
no journal, ,
no abstracts in English
Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro*; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari*; Matsumura, Hiroyoshi*; Adachi, Hiroaki*; et al.
no journal, ,
To understand the catalytic mechanism of HIV-1 protease, we have determined the crystal structure of HIV-1 protease in complex with a transition state mimetic inhibitor, KNI-272 by neutron crystallography. Our results indicates that the carbonyl group of allophenylnorstatine in KNI-272 forms a significant hydrogen bond with protonated Asp 25, and the hydrogen atom from the hydroxyl group of allophenylnorstatine forms a remarkable hydrogen bond with the deprotonated Asp125. These results show direct evidence that Asp25 provides a proton to carbonyl group of substrate and Asp125 contributes to activate the attacking water molecule as a nucleophile.
Adachi, Motoyasu; Ohara, Takashi; Kurihara, Kazuo; Tamada, Taro; Honjo, Eijiro*; Okazaki, Nobuo; Arai, Shigeki; Shoyama, Yoshinari*; Matsumura, Hiroyoshi*; Sugiyama, Shigeru*; et al.
no journal, ,
In this study, we determined crystal structures of HIV-1 protease complexed with inhibitor by neutron and X-ray crystallography. Finally, we refined the structures to R-factor of 17.3% and free R-factor 20.3% by neutron crystallography and to R-factor of 10.4 % and free R-factor 12.4% by X-ray crystallography. The result shows that Asp 25 residue is protonated and Asp 125 is deprotonated. These information is important to resolve catalytic mechanism and design of new potent inhibitor.