title: Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.
abstract: The drug pentamidine inhibits calcium-dependent complex formation with p53 ((Ca)S100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of (Ca)S100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the "FF-gate". For symmetric pentamidine analogues ((Ca)S100B·5a, (Ca)S100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue ((Ca)S100B·17), this same channel was open. The (Ca)S100B·17 structure illustrates, for the first time, a pentamidine analog capable of binding the "open" form of the "FF-gate" and provides a means to block all three "hot spots" on (Ca)S100B, which will impact next generation (Ca)S100B·p53 inhibitor design.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Cavalier
authors.affiliation: Computer Aided Drug Design Center, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Mohd Imran
authors.initials: MI
authors.lastname: Ansari
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Pierce
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wilder
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: McKnight
authors.affiliation: Computer Aided Drug Design Center, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: E Prabhu
authors.initials: EP
authors.lastname: Raman
authors.affiliation: NE-CAT , Argonne Illinois 60439, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Neau
authors.affiliation: Computer Aided Drug Design Center, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Padmavani
authors.initials: P
authors.lastname: Bezawada
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Milad J
authors.initials: MJ
authors.lastname: Alasady
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Charpentier
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Varney
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Institute for Bioscience and Biotechnology Research , 9600 Gudelsky Drive, Rockville, Maryland 20850, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Toth
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Computer Aided Drug Design Center, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Computer Aided Drug Design Center, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Weber
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010419:Pentamidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D064568:S100 Calcium Binding Protein beta Subunit; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D010419:Pentamidine