Sussman’s current research focuses on nervous system proteins, especially acetylcholinesterase (AChE), whose 3D structure was first determined in his lab. This structure revealed [4-8]: (a) AChE is a prototype of the α/β hydrolase fold ; (b) π-cation interactions play a key role in binding of acetylcholine (ACh) and ligands to AChE ; (c) Its ACh-binding site assisted in structure-based design of promising leads for novel anti-Alzheimer’s drugs; (d) discovered a highly asymmetric charge distribution  conserved in ‘cholinesterase-like adhesion molecules’ (CLAMs), and showed that their cytoplasmic domains are ‘intrinsically unfolded’  with implications for neural development and plasticity, and led to an algorithm, Foldindex©, for predicting whether a protein sequence will fold; (f) revealed a novel anchoring device for AChE involving superhelical assembly of its subunits around a polyproline-II helix ; and (g) illuminated the specific chemical and structural damage to proteins produced by synchrotron radiation, e.g. cleavage of a specific disulfide bond even at cryo temperatures .
He has investigated the molecular basis for halophilicity  and halotolerance , shedding light on the molecular basis of how proteins function over extreme ranges of salt-concentration, with unexpected implications for kidney diseases. Recently, he determined the structures of acid-β-glucosidase , a protein defective in Gaucher disease, paving the way to novel therapeutic approaches, and of paraoxonase , a protein relevant to treatment of atherosclerosis.
(1) J.L Sussman & S.-H. Kim (1976) "Three-dimensional structure of a transfer RNA in two crystal forms" Science 192, 853-858 PMID 775636
(2) J.L. Sussman, S.R. Holbrook, G.M. Church & S.-H. Kim (1977) "A structure-factor least squares refinement procedure for macromolecular structures using constrained and restrained parameters" Acta Cryst. A33, 800-804 Abstract
(3) L. Joshua-Tor, D. Rabinovich, H. Hope, F. Frolow, E. Appella & J.L. Sussman (1988) "The three-dimensional structure of a DNA duplex containing looped out bases" Nature 334, 82-84 PMID 3386751
(4) J.L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman, L. Toker & I. Silman (1991) "Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein" Science 253, 872-879. PMID 1678899
(5) D.R. Ripoll, C.H. Faerman, P. Axelsen, I. Silman & J.L. Sussman (1993) "An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase" Proc. Natl. Acad. Sci. USA 90, 5128-5132 PMID 8506359
(6) T. Zeev-Ben-Mordehai, E.H. Rydberg, A. Solomon, L. Toker, S. Botti, V.J. Auld, I. Silman & J.L. Sussman (2003) "The intracellular domain of the drosophila cholinesterase-like neural adhesion protein, gliotactin, is natively unfolded" Proteins 53, 758-767 PMID 14579366
(7) H. Dvir, M. Harel, S. Bon, W.-Q. Liu, M. Vidal, C. Garbay, J.L. Sussman, J. Massoulié & I. Silman (2004) "The synaptic acetylcholinesterase tetramer assembles around a polyproline-II helix" EMBO J. 23, 4394-4405 PMID 15526038
(8) Weik, M., Ravelli, R.B.G., Kryger, G., McSweeney, S., Raves, M., Harel, M., Gros, P., Silman, I., Kroon, J. & Sussman, J.L. (2000) "Specific chemical and structural damage to proteins produced by synchrotron radiation" Proc. Natl. Acad. Sci. USA 97, 623-628. PMID 10639129
(9) O. Dym, M. Mevarech & J.L. Sussman (1995) "Structural features that stabilize Halophilic malate dehydrogenase from an Archaebacterium" Science 267, 1344-1346 Abstract
(10) L. Premkumar, H.M. Greenblatt, U. Bagashwar, T. Savchenkoa, I. Gokhmana, J.L. Sussman & A. Zamir (2005) "3D structure of a halotolerant algal carbonic anhydrase predicts halotolerance of a mammalian homolog" Proc. Natl. Acad. Sci. USA 102, 7493-7498 PMID 15894606
(11) H. Dvir, M. Harel, A.H. McCarthy, L. Toker, I. Silman, A.H. Futerman & J.L. Sussman. X-ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease (2003) EMBO Rep. 4, 704-709 PMID 15098021
(12) M. Harel, A. Aharoni, L. Gaidukov, B. Brumshtein, O. Khersonsky, S. Yagur, R. Meged, H. Dvir, R.B.G. Ravelli, A. McCarthy, L. Toker, I. Silman, J.L. Sussman & D.S. Tawfik (2004) "3D-Structure, mechanism and evolution of serum paraoxonases – a family of detoxifying and anti-atherosclerotic enzymes" Nat. Struct. Mol. Biol. 11, 412-419 PMID 15098021
US Patent Issued to Yeda Research And Development on Dec. 21 for "Partially Deglycosylated Glucocerebrosidase Polypeptide and Crystals Thereof" (American, Israeli Inventors)
Dec 26, 2010; ALEXANDRIA, Va., Dec. 26 -- United States Patent no. 7,855,063, issued on Dec. 21, was assigned to Yeda Research And Development...
Proteopedia - a scientific 'wiki' bridging the rift between three-dimensional structure and function of biomacromolecules.(Software)
Aug 03, 2008; Authors: Eran Hodis [1,2,7]; Jaime Prilusky ; Eric Martz ; Israel Silman [2,5]; John Moult ; Joel L Sussman...