Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

Cheng Chung Lee; Chih Jung Kuo; Min Feng Hsu; Po Huang Liang; Jim Min Fang; Jiun Jie Shie; Andrew H.J. Wang

doi:10.1016/j.febslet.2007.10.048

Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

Cheng Chung Lee, Chih Jung Kuo, Min Feng Hsu, Po Huang Liang, Jim Min Fang, Jiun Jie Shie, Andrew H.J. Wang

Research output: Contribution to journal › Article › peer-review

52 Citations (Scopus)

Abstract

Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease of severe acute respiratory syndrome (SARS)-associated coronavirus were analyzed crystallographically. The complex structures reveal two major inhibition modes: Hg²⁺-PMA is coordinated to C⁴⁴, M⁴⁹ and Y⁵⁴ with a square planar geometry at the S3 pocket, whereas each Zn²⁺ of the four zinc-inhibitors is tetrahedrally coordinated to the H⁴¹-C¹⁴⁵ catalytic dyad. For anti-SARS drug design, this Zn²⁺-centered coordination pattern would serve as a starting platform for inhibitor optimization.

Original language	English
Pages (from-to)	5454-5458
Number of pages	5
Journal	FEBS Letters
Volume	581
Issue number	28
DOIs	https://doi.org/10.1016/j.febslet.2007.10.048
Publication status	Published - Nov 27 2007
Externally published	Yes

Keywords

Metal ion
Protease inhibitor
SARS

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

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10.1016/j.febslet.2007.10.048

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title = "Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors",

abstract = "Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease of severe acute respiratory syndrome (SARS)-associated coronavirus were analyzed crystallographically. The complex structures reveal two major inhibition modes: Hg2+-PMA is coordinated to C44, M49 and Y54 with a square planar geometry at the S3 pocket, whereas each Zn2+ of the four zinc-inhibitors is tetrahedrally coordinated to the H41-C145 catalytic dyad. For anti-SARS drug design, this Zn2+-centered coordination pattern would serve as a starting platform for inhibitor optimization.",

keywords = "Metal ion, Protease inhibitor, SARS",

author = "Lee, {Cheng Chung} and Kuo, {Chih Jung} and Hsu, {Min Feng} and Liang, {Po Huang} and Fang, {Jim Min} and Shie, {Jiun Jie} and Wang, {Andrew H.J.}",

note = "Funding Information: We acknowledge the National Synchrotron Radiation Research Center of Taiwan, SPring-8 of Japan for beam time allocation. We thank Dr. T.-P. Ko for critical review of the manuscript. This work was supported by grants from Academia Sinica and the National Science Council, Taiwan NSC-93-3112-B-001-011-Y to A.H.-J. Wang for the National Core Facility of High-Throughput Protein Crystallography at Academia Sinica, Taiwan. ",

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language = "English",

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T1 - Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

AU - Lee, Cheng Chung

AU - Kuo, Chih Jung

AU - Hsu, Min Feng

AU - Liang, Po Huang

AU - Fang, Jim Min

AU - Shie, Jiun Jie

AU - Wang, Andrew H.J.

N1 - Funding Information: We acknowledge the National Synchrotron Radiation Research Center of Taiwan, SPring-8 of Japan for beam time allocation. We thank Dr. T.-P. Ko for critical review of the manuscript. This work was supported by grants from Academia Sinica and the National Science Council, Taiwan NSC-93-3112-B-001-011-Y to A.H.-J. Wang for the National Core Facility of High-Throughput Protein Crystallography at Academia Sinica, Taiwan.

PY - 2007/11/27

Y1 - 2007/11/27

N2 - Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease of severe acute respiratory syndrome (SARS)-associated coronavirus were analyzed crystallographically. The complex structures reveal two major inhibition modes: Hg2+-PMA is coordinated to C44, M49 and Y54 with a square planar geometry at the S3 pocket, whereas each Zn2+ of the four zinc-inhibitors is tetrahedrally coordinated to the H41-C145 catalytic dyad. For anti-SARS drug design, this Zn2+-centered coordination pattern would serve as a starting platform for inhibitor optimization.

AB - Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease of severe acute respiratory syndrome (SARS)-associated coronavirus were analyzed crystallographically. The complex structures reveal two major inhibition modes: Hg2+-PMA is coordinated to C44, M49 and Y54 with a square planar geometry at the S3 pocket, whereas each Zn2+ of the four zinc-inhibitors is tetrahedrally coordinated to the H41-C145 catalytic dyad. For anti-SARS drug design, this Zn2+-centered coordination pattern would serve as a starting platform for inhibitor optimization.

KW - Metal ion

KW - Protease inhibitor

KW - SARS

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Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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