title: An Analysis of MIF Structural Features that Control Functional Activation of CD74.
abstract: For more than 15 years, the tautomerase active site of macrophage migration inhibitory factor (MIF) and its catalytic residue Pro1 have been being targeted for the development of therapeutics that block activation of its cell surface receptor, CD74. Neither the biological role of the MIF catalytic site nor the mechanistic details of CD74 activation are well understood. The inherently unstable structure of CD74 remains the biggest obstacle in structural studies with MIF for understanding the basis of CD74 activation. Using a novel approach, we elucidate the mechanistic details that control activation of CD74 by MIF surface residues and identify structural parameters of inhibitors that reduce CD74 biological activation. We also find that N-terminal mutants located deep in the catalytic site affect surface residues immediately outside the catalytic site, which are responsible for reduction of CD74 activation.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pantouris
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Mansoor Ali
authors.initials: MA
authors.lastname: Syed
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Chengpeng
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rajasekaran
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Thomas Yoonsang
authors.initials: TY
authors.lastname: Cho
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Rosenberg
authors.affiliation: Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: elias.lolis@yale.edu.
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Lolis
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain