The Rigby laboratory continues to use modern structural biology and biophysical approaches to evaluate protein-protein, protein-membrane, protein-ligand and most recently protein-DNA interactions that are critical in mediating macromolecular complex formation in the areas of blood coagulation, apoptosis, gene regulation and cancer. In addition to his laboratories use of NMR spectroscopy, Dr Rigby has recently brought computational drug discovery initiatives into his laboratory and the BIDMC community at large. The continued implementation of NMR based approaches in hit-through-lead drug discovery in the laboratory of Dr Rigby and others is founded upon NMR applications that continually assess structure activity relationships, which iteratively “guide” the assembly of several weakly interacting fragments or small molecules through chemical links. His laboratory is focused on the recent advances in structure based computational screening approaches, in which they have highlighted the successful integration of in silico virtual screens with NMR-based techniques. The applications of this powerful, combinatorial approach for the evaluation of well-characterized target space as well as its application to unique chemical space such as those interaction interfaces listed above that have recently been shown to be tractable to small molecule intervention. These studies involve the implementation of novel computational strategies that explore new three-dimensional space using the power of UNIX and linux computational clusters that use several software packages including: Tripos, MOE, Molcad, Yassara, and InsightII.
In addition, my laboratory is determining the 3D structure of several novel Conus neurotoxins, conotoxins, which we will continue to use in defining critical receptor ligand interactions that we believe will permit the identification of the interaction interface created between these isoform-specific antagonists and the N-methyl-D-aspartate receptor and L-type calcium channels.
Grant MA, Hansson K, Furie BC, Furie B, Stenflo J, Rigby AC. The metal-free and calcium-bound structures of a gamma-carboxyglutamic acid-containing contryphan from Conus marmoreus, glacontryphan-M. J Biol Chem. 2004 279(31):32464-73.(cover article)
Huang M*, Rigby AC*, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC. Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struc Biol 2003;10(9):751-6. (*co-first authors)
Morelli XJ, Palma PN, Guerlesquin F, Rigby AC. A Novel Approach for Assessing Macromolecular Complexes Combining Soft Docking Calculations with NMR Data. Protein Science 2001;10:2131-7.
Grant MA, Morelli X, Rigby AC. Conotoxins and Structural Biology: A Prospective Paradigm for Drug Discovery.
Current Protein and Peptide Science. 2004 August;5(4):235-248. Cover Article
Rigby AC, Hambe B, Czerwiec E, Baleja JD, Furie BC, Furie B, Stenflo J. A Conotoxin from Conus Textile with Unusual Posttranslational Modifications Reduces Presynaptic Ca2 Influx. Proc Natl Acad Sci 1999;96:5758-5763.
External Recognition:
1997 Federation of American Society for Experimental Biology Young
Investigator Award, Vitamin K Conference
1999-2001 American Heart Association;
Structural Investigation of the Gla domain of Human Prothrombin;
Defining the Calcium and Phospholipid Binding Determinants
2001-2004 National, American Heart Association; Grant-in-Aid
A Structure/Function Investigation of the Anticoagulant
Protein SProtein S
2001-2005 National Science Foundation
Structure/Function Investigation of Gamma-Carboxyglutamic Acid-Containing Conotoxins
2002-2006 National Institutes of Health RO1
Structure/ Function Study of the Anticoagulant, Protein S
2004 Pfizer Atorvastatin Research Award
2005 Pfizer Atorvastatin Research Award
NSF: MCB Grant Review Committee
NIH: SBIR/STTR Study Section
NIH: BCMB-B Study Section
Major Collaborative Activities:
Ets-1 DNA interactions: Dr Peter Oetggen
HMGA1-DNA interactions: Dr Mark Perrella, BWH
cGK1alpha-MBS interactions: Dr Mike Mendelsohn
Perforin C2 domain: Dr Judy Lieberman, CBR
