The Rockefeller University

Mcgill University

Stephen K Burley

Jeffrey M Friedman

Jeffrey L Halaas

Ketan Gajiwala

Ricardo Proenca

Yiying Zhang

Nahum Sonenberg

Joseph Marcotrigiano

Margherita Maffei

Anne-Claude Gingras

The present invention relates generally to the control of body weight of animals including mammals and humans, and more particularly to nucleic acids encoding materials identified herein as modulators of weight. In its broadest aspect, the present invention relates to the elucidation and discovery of nucleotide sequences, and proteins putatively expressed by such nucleotides, that demonstrate the ability to participate in the control of mammalian body weight. The nucleotide sequences in object represent the genes corresponding to the murine and human ob gene, that have been postulated to play a critical role in the regulation of body weight and adiposity. Preliminary data, presented herein, suggests that the polypeptide product of the gene in question functions as a hormone. The present invention further provides nucleic acid molecules for use as molecular probes, or as primers for polymerase chain reaction (PCR) amplification, i.e., synthetic or natural oligonucleotides.

Nucleic acids encoding modulators of body weight

The present invention relates generally to the control of body weight of animals including mammals and humans, and more particularly to materials identified herein as modulators of weight, and to the diagnostic and therapeutic uses to which such modulators may be put. In its broadest aspect, the present invention relates to the elucidation and discovery of nucleotide sequences, and proteins putatively expressed by such nucleotides or degenerate variations thereof, that demonstrate the ability to participate in the control of mammalian body weight. The nucleotide sequences in object represent the genes corresponding to the murine and human ob gene, that have been postulated to play a critical role in the regulation of body weight and adiposity. Preliminary data, presented herein, suggests that the polypeptide product of the gene in question functions as a hormone. The present invention further provides nucleic acid molecules for use as molecular probes, or as primers for polymerase chain reaction (PCR) amplification, i.e., synthetic or natural oligonucleotides. In further aspects, the present invention provides a cloning vector, which comprises the nucleic acids of the invention; and a bacterial, insect, or a mammalian expression vector, which comprises the nucleic acid molecules of the invention, operatively associated with an expression control sequence. Accordingly, the invention further relates to a bacterial or a mammalian cell transfected or transformed with an appropriate expression vector, and correspondingly, to the use of the above mentioned constructs in the preparation of the modulators of the invention. Also provided are antibodies to the ob polypeptide. Moreover, a method for modulating body weight of a mammal is provided. In specific examples, genes encoding two isoforms of both the murine and human ob polypeptides are provided.

OB polypeptides, modified forms and derivatives

A detailed three-dimensional structure for the least abundant of the general translation initiation factors in eukaryotes, eIF4E, complexed with a ligand is disclosed. The novel N-terminal truncated eIF4Es which were constructed so as to omit a significant portion of the flexible N-terminal tail of the eIF4E are also part of the present invention. In addition, the crystals of the protein-ligand complexes containing the N-terminal truncated eIF4Es are also included. Furthermore, methods of identifying antagonists of the eIF4E protein which can be used to regulate protein synthesis in cells are also disclosed.

Crystal of a protein-ligand complex containing an N-terminal truncated

Mammalian ob polypeptides capable of modulating body weight,

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New York, NY, United States of America

Stephen K Burley