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Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach

Published online by Cambridge University Press:  08 December 2000

YUAN-PING PANG
Affiliation:
Mayo Clinic Cancer Center, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905 Tumor Biology Program, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905 Molecular Neuroscience Program, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905
KUN XU
Affiliation:
Tumor Biology Program, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905
JAMAL EL YAZAL
Affiliation:
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905
FRANKLYN G. PRENDERGAST
Affiliation:
Mayo Clinic Cancer Center, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905 Tumor Biology Program, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, Minnesota 55905
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Abstract

Farnesyltransferase (FT) inhibitors can suppress tumor cell proliferation without substantially interfering with normal cell growth, thus holding promise for cancer treatment. A structure-based approach to the design of improved FT inhibitors relies on knowledge of the conformational flexibility of the zinc-containing active site of FT. Although several X-ray structures of FT have been reported, detailed information regarding the active site conformational flexibility of the enzyme is still not available. Molecular dynamics (MD) simulations of FT can offer the requisite information, but have not been applied due to a lack of effective methods for simulating the four-ligand coordination of zinc in proteins. Here, we report in detail the problems that occurred in the conventional MD simulations of the zinc-bound FT and a solution to these problems by employing a simple method that uses cationic dummy atoms to impose orientational requirement for zinc ligands. A successful 1.0 ns (1.0 fs time step) MD simulation of zinc-bound FT suggests that nine conserved residues (Asn127α, Gln162α, Asn165α, Gln195α, His248β, Lys294β, Leu295β, Lys353β, and Ser357β) in the active site of mammalian FT are relatively mobile. Some of these residues might be involved in the ligand-induced active site conformational rearrangement upon binding and deserve attention in screening and design of improved FT inhibitors for cancer chemotherapy.

Type
Research Article
Information
Protein Science , Volume 9 , Issue 10 , October 2000 , pp. 1857 - 1865
Copyright
© 2000 The Protein Society

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