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Mol. Cells 2009; 27(6): 667-671

Published online June 12, 2009

https://doi.org/10.1007/s10059-009-0088-x

© The Korean Society for Molecular and Cellular Biology

Crystal Structure of Rattus norvegicus Visfatin/PBEF/Nampt in Complex with an FK866-Based Inhibitor

Gil Bu Kang, Man-Ho Bae, Mun-Kyoung Kim, Isak Im, Yong-Chul Kim, and Soo Hyun Eom

Received: February 13, 2009; Revised: April 16, 2009; Accepted: April 17, 2009

Abstract

Visfatin (Nampt/PBEF) plays a pivotal role in the salvage pathway for NAD+ biosynthesis. Its potent inhibitor, FK866, causes cellular NAD+ levels to decline, thereby inducing apoptosis in tumor cells. In an effort to improve the solubility and binding interactions of FK866, we designed and synthesized IS001, in which a ribose group is attached to the FK866 pyridyl ring. Here, we report the crystal structure of rat visfatin in complex with IS001. Like FK866, IS001 is positioned at the dimer interface, and all of the residues that interact with IS001 are involved in hydrophobic or ?-?-stacking interactions. However, we were unable to detect any strong interac-tions between the added ribose ring of IS001 and visfatin, which implies that a bulkier modifying group is necessary for a tight interaction. This study provides additional structure-based information needed to optimize the design of visfatin inhibitors.

Keywords crystal structure, FK866, nicotinamide phosphoribosyltransferase (Nampt), pre-B-cell colony-enhancing factor (PBEF), visfatin

Article

Research Article

Mol. Cells 2009; 27(6): 667-671

Published online June 30, 2009 https://doi.org/10.1007/s10059-009-0088-x

Copyright © The Korean Society for Molecular and Cellular Biology.

Crystal Structure of Rattus norvegicus Visfatin/PBEF/Nampt in Complex with an FK866-Based Inhibitor

Gil Bu Kang, Man-Ho Bae, Mun-Kyoung Kim, Isak Im, Yong-Chul Kim, and Soo Hyun Eom

Received: February 13, 2009; Revised: April 16, 2009; Accepted: April 17, 2009

Abstract

Visfatin (Nampt/PBEF) plays a pivotal role in the salvage pathway for NAD+ biosynthesis. Its potent inhibitor, FK866, causes cellular NAD+ levels to decline, thereby inducing apoptosis in tumor cells. In an effort to improve the solubility and binding interactions of FK866, we designed and synthesized IS001, in which a ribose group is attached to the FK866 pyridyl ring. Here, we report the crystal structure of rat visfatin in complex with IS001. Like FK866, IS001 is positioned at the dimer interface, and all of the residues that interact with IS001 are involved in hydrophobic or ?-?-stacking interactions. However, we were unable to detect any strong interac-tions between the added ribose ring of IS001 and visfatin, which implies that a bulkier modifying group is necessary for a tight interaction. This study provides additional structure-based information needed to optimize the design of visfatin inhibitors.

Keywords: crystal structure, FK866, nicotinamide phosphoribosyltransferase (Nampt), pre-B-cell colony-enhancing factor (PBEF), visfatin

Mol. Cells
Sep 30, 2023 Vol.46 No.9, pp. 527~572
COVER PICTURE
Chronic obstructive pulmonary disease (COPD) is marked by airspace enlargement (emphysema) and small airway fibrosis, leading to airflow obstruction and eventual respiratory failure. Shown is a microphotograph of hematoxylin and eosin (H&E)-stained histological sections of the enlarged alveoli as an indicator of emphysema. Piao et al. (pp. 558-572) demonstrate that recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) significantly reduces the extended airspaces of the emphysematous alveoli by increasing the levels of TGF-β receptor I and SIRT1/6, as a previously unrecognized mechanism in human alveolar epithelial cells, and consequently mitigates COPD.

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