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Structural Biology

Our research program seeks to understand, in molecular detail, fundamental cellular processes that occur at the membrane interface. We utilize a multidisciplinary approach in our program. X-ray crystallography is our main tool to obtain high-resolution structures and macromolecular mechanisms are elucidated with complementary biochemical and biophysical studies including NMR, Small Angle X-Ray Scattering and EM.
Three fundamental membrane-related systems are the focus of our program:

(i) Folding and Insertion of Membrane Proteins in the Bacterial and Mitochondrial Outer Membrane:听We seek to understand the molecular mechanisms by which chaperones and the BAM membrane protein complex cooperate to promote folding and specific insertion of b-barrel OMPs into bacterial and mitochondrial outer membranes.

(ii) Modification of the Bacterial Outer Membranes Mediating Antibiotic Resistance:听Lipid-A modification with Ara4N confers resistance antimicrobial peptides of the innate immune system as well as antibiotics such as colistin. The focus of our research is to determine the structure and mechanism of enzymes essential for Lipid-A modification with Ara4N as a key for the design and evaluation of specific inhibitors.

(iii) Signaling Pathways at the Membrane Interface: Membrane-bound Guanylyl Cyclases:听We seek to determine the molecular basis for disease causing mutations in GCs as well as validating the hypothesis of a conserved activation mechanism for all members of the membrane-GCs family.

Walton, T. A. &听Sousa, M. C.听鈥淐rystal Structure of Skp. A Prefoldin-like Chaperone that Protects Soluble and Membrane Proteins from Aggregation鈥�
Molecular Cell.听(2004)听15(3):367-74.

Gatzeva-Topalova, PZ; May, A and听Sousa M.C.听鈥淐rystal Structure of听E. coli听ArnA (PmrI) Decarboxylase Domain. A Key Enzyme for LipidA Modification with 4-amino-4deoxy-L-arabinose and Polymyxin Resistance.鈥�
叠颈辞肠丑别尘颈蝉迟谤测.听(2004) 43 (42):13370-9. PMCID: PMC2680612

Gatzeva-Topalova, PZ; May, A and听Sousa M.C. 鈥淐rystal Structure and Mechanism of听E. coli听ArnA (PmrI) Transformylase Domain. An Enzyme for Lipid A Modification with 4-amino-4-deoxy-L-arabinose and Polymyxin Resistance "
叠颈辞肠丑别尘颈蝉迟谤测.听(2005) 44 (14): 5328-5338. PMCID: PMC2583347

Gatzeva-Topalova, PZ; May, A and听Sousa M.C. 鈥淪tructure and Mechanism Of ArnA-A Key Enzyme For Polymyxin Resistance. Conformational Change Implies Ordered Dehydrogenase Mechanism."
Structure.听(2005) 13 (6): 929-42听[Cover Feature].

Stephen, R.; Palczewski, K. and听Sousa M.C.听鈥淭he Crystal Structure of GCAP3 Suggests Molecular Mechanism of GCAP鈥搇inked Cone Dystrophies.鈥�
J. Mol. Biol.听(2006) 359 (2): 266-275.

Stephen, R.; Bereta, G.; Golczak, M.; Palczewski, K. and听Sousa M.C.听鈥淪tabilizing Function for Myristoyl Group Revealed by the Crystal Structure of a Neuronal Calcium Sensor, Guanylate-Cyclase-Activating Protein 1鈥�
Structure听(2007) 15 (11): 1392-1402. PMCID: PMC2556213

Gatzeva-Topalova, P.Z.; Walton, T.A. and听Sousa M.C.听鈥淐rystal Structure of YaeT - Conformational Flexibility and Substrate Recognition鈥�.
Structure.听(2008) 16 (12): 1873-1881. PMCDI: PMC2642521.

Walton, T.A.; Sandoval, C.M.; Fowler, C.A.; Pardi, A. and听Sousa M.C.听鈥淭he Cavity-Chaperone Skp Protects its Substrate from Aggregation but Allows Independent Folding of Substrate Domains鈥�
PNAS (direct submission).听(2009) 106 (10): 1772-1777. PMCID: PMC2644113

Gatzeva-Topalova, P.Z.; Warner, L.R.; Pardi, A. and听Sousa M.C. 鈥淪tructure and Flexibility of the Complete Periplasmic Domain of BamA. The Protein Insertion Machine of the Outer Membrane.鈥�
厂迟谤耻肠迟耻谤别.听(2010) 18(11):1492-501. PMCID: PMC2991101

Sandoval, C.M.; Baker S.L.; Jansen, K.; Metzner, S.I. and听Sousa M.C. 鈥淐rystal Structure of BamD. An Essential Component of the b-Barrel Assembly Machinery of Gram Negative Bacteria.鈥�
J. Mol. Biol.听(2011) in press. PMCID:听PMC3098899

Warner, L.R; Varga, K.; Lange, O.F.; Baker, S.L.; Baker, D.;听Sousa, M.C.听and Pardi A.听
鈥淪tructure of the BamC two-domain protein obtained by Rosetta with a limited NMR data set.鈥�
J. Mol. Biol.听(2011) 411 (1): 83-95. PMCID:听PMC3182476