![]() This is in sharp contrast with other Zinc dependent metalloproteases such as Adamalysin II, and TACE, for which three-dimensional structures have been determined. However, use of this powerful methodology requires the three-dimensional structure of the target protein and, heretofore, little to no information has been provided regarding the three-dimensional structure of ADAM33. Structure based drug design is one way to optimize the success of such drug discovery. Due to its genetic linkage to asthma, ADAM33 has become a promising target protein for use in identifying pharmaceuticals to treat asthma. Moreover, heretofore, the ADAM33 protein domains, including the catalytic domain, had not been specifically delineated and isolated. However, little specific information has been provided regarding the catalytic activity of ADAM33. Others also have disclosed human and mouse ADAM33 nucleic acid and amino acid sequences. 6,420,154 B1 discloses a human nucleic acid sequence that subsequently was shown to encode ADAM33, along with the corresponding amino acid sequence. The ADAM family of proteins is a class of type-I transmembrane proteins that share a unique domain structure composed of a signal sequence, a pro domain, a metalloprotease/catatlytic domain, a disintegrin domain, a cysteine-rich domain, an epidermal growth factor-like domain, a transmembrane and a cytoplasmic domain. ADAM33 is a member of the “A Disintegrin And Metalloprotease” (ADAM) family of proteins which comprises over thirty such proteins, including the well characterized ADAM17, the TNF-&agr converting enzyme (TACE). Recently, the gene encoding a membrane anchored protein known as ADAM33 has been shown to be linked to asthma by positional cloning in an outbred population. What is known is that asthmatics have a genetic predisposition for the disease, and environmental factors serve to either trigger or protect against this immunological dysregulation. Both genetic and environmental factors play key roles in inducing this T-cell-mediated inflammation, though the actual mechanism has yet to be delineated. The immediate cause for the thickening of the airway walls, smooth muscle contraction, and narrowing of the airways observed in asthmatics is an inflammation mediated by T-cells. Common symptoms of asthma include recurrent episodes of coughing, wheezing and breathlessness. Asthma is characterized by life-threatening attacks due to episodic obstructions to, or abnormal narrowing of the airways in response to otherwise innocuous stimuli. Despite this strong commitment, to date the treatments employed only control the symptoms. Not surprisingly, the dramatic increase in the number of asthmatics in industrialized nations has resulted in a concomitant expenditure of resources to treat this condition. Indeed, 10-20% of the population of industrialized countries currently suffers from asthma. Though the occurrence of this respiratory disorder has been noted for over two thousand years, during the past twenty years industrialized nations have experienced an increase in asthma sufferers that approaches epidemic proportions. Asthma is a chronic respiratory disorder that afflicts hundreds of millions of people throughout the world. In addition, the present invention pertains to methods of using the X-ray diffractable crystals of this catalytic domain in structure based drug design to identify compounds that can modulate the activity of the protein. The present invention further pertains to methods of growing X-ray diffractable crystals of this catalytic domain. The present invention also pertains to a process of obtaining specific samples of this catalytic domain that are amenable to forming homogenous crystals for X-ray crystallization analysis. The present invention pertains to a catalytic domain of a protein that is characterized by having a disintegrin and metalloprotease domain (ADAM). ![]() ![]() These applications are hereby incorporated by reference in their entirety. Provisional Application 60/434,830, filed Dec. This application claims the benefit of U.S.
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