Crystallization of IGF-1

• US 7,433,788 B2
• Filed: 06/20/2006
• Issued: 10/07/2008
• Est. Priority Date: 02/09/2001
• Status: Expired due to Fees

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Ultsch, Mark, Schaffer, Michelle, Vajdos, Felix
• Primary Examiner(s): Steadman; David J.
• Assistant Examiner(s): Lee; Jae W
• Application Number:
  US11/471,897
• Publication Number:
  US 20060281905A1
• Time in Patent Office: 840 Days
• Field of Search: None
• US Class Current: 702/27
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/65 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
• CPC Class Codes: C07K 2299/00 Coordinates from 3D structures of peptides, e.g. proteins or enzymes

Abstract

Crystalline IGF-1 is provided along with a method for production thereof. Crystallizing IGF-1 comprises the steps of mixing an aqueous solution comprising IGF-1 with a reservoir solution comprising a precipitant to form a mixture; and crystallizing the mixture, optionally also recrystallizing and isolating the crystalline IGF-1. In addition, a method for identifying IGF-1 indirect agonists is provided using a detergent as a standard for the level of inhibition of binding of IGFBP-1 or IGFBP-3 to IGF-1 and/or using the coordinates of the binding pockets of IGF-1 to which a candidate indirect agonist binds for structure-based drug design.

Claims

1. A method of identifying an agonist or antagonist of insulin-like growth factor 1 (IGF-1) of SEQ ID NO:

1, comprising (i) obtaining a crystal formed by said IGF-1 of SEQ ID NO;

1 that diffracts x-ray radiation to produce a diffraction pattern representing the three-dimensional structure of the IGF-1 of SEQ ID NO;

1, including a receptor binding region comprising residues Tyr24, Thr29, Tyr31, and Tyr60 of said IGF-1 of SEQ ID NO;

1, and has approximately the following cell constants a=31.831 Å

, b=71.055 Å

, c=65.995 Å

, and a space group of C222₁, and α

=β

=γ

, (ii) employing said three-dimensional structure to identify a compound that has a receptor-binding region that assumes the structure of or binds to said receptor binding region, and (iii) confirming that said compound acts as an IGF-1 agonist or antagonist thereby identifying said agonist or antagonist.