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J. Biol. Chem., Vol. 279, Issue 49, 50684-50690, December 3, 2004

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"Chemical Analogues" of HLA-DM Can Induce a Peptide-receptive State in HLA-DR Molecules^*

Viviana Marin-Esteban, Kirsten Falk, and Olaf Rötzschke

From the Max Delbrück Center for Molecular Medicine, Robert Rösslestrasse 10, 13125 Berlin, Germany

We had recently identified small molecular compounds that are able to accelerate the ligand exchange reactions of HLA-DR molecules. Here we show that this acceleration is due to the induction of a "peptide-receptive" state. Dissociation experiments of soluble HLA-DR2·CLIP (class II-associated invariant chain peptide) complex and peptide-binding studies with "nonreceptive" empty HLA-DR1 and -DR2 molecules revealed that the presence of a small phenolic compound carrying an H-bond donor group (–OH) results in the drastic increase of both off- and on-rates. The rate-limiting step for ligand exchange, the transition of the major histocompatibility complex molecule from a nonreceptive into the receptive state, is normally mediated by interaction with the chaperone HLA-DM. In this respect, the effect of small molecules resembles that of the natural catalyst, except that they are still active at neutral pH. These "chemical analogues" of HLA-DM can therefore modulate the response of CD4+ T cells by editing the antigen composition of surface-bound class II major histocompatibility complex on living antigen-presenting cells.

Received for publication, July 7, 2004 , and in revised form, September 15, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Ph.D. student stipend awarded from the Max Delbrück Center.

To whom correspondence may be addressed. Tel.: 49-30-9406-3664; Fax: 49-30-9406-2394; E-mail: falk{at}mdc-berlin.de; roetzsch{at}mdc-berlin.de.

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