Paul A Sigala

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Understanding the electrostatic forces and features within highly heterogeneous, anisotropic, and chemically complex enzyme active sites and their connection to biological catalysis remains a longstanding challenge, in part due to the paucity of incisive experimental probes of electrostatic properties within proteins. To quantitatively assess the landscape(More)
Malaria parasites generate vast quantities of heme during blood stage infection via hemoglobin digestion and limited de novo biosynthesis, but it remains unclear if parasites metabolize heme for utilization or disposal. Recent in vitro experiments with a heme oxygenase (HO)-like protein from Plasmodium falciparum suggested that parasites may enzymatically(More)
Enzymes are classically proposed to accelerate reactions by binding substrates within active-site environments that are structurally preorganized to optimize binding interactions with reaction transition states rather than ground states. This is a remarkably formidable task considering the limited 0.1-1 A scale of most substrate rearrangements. The(More)
Hydrogen bonds play major roles in biological structure and function. Nonetheless, hydrogen-bonded protons are not typically observed by X-ray crystallography, and most structural studies provide limited insight into the conformational plasticity of individual hydrogen bonds or the dynamical coupling present within hydrogen bond networks. We report the NMR(More)
For over a century, heme metabolism has been recognized to play a central role during intraerythrocytic infection by Plasmodium parasites, the causative agent of malaria. Parasites liberate vast quantities of potentially cytotoxic heme as a by-product of hemoglobin catabolism within the digestive vacuole, where heme is predominantly sequestered as inert(More)
Hydrogen bond networks are key elements of protein structure and function but have been challenging to study within the complex protein environment. We have carried out in-depth interrogations of the proton transfer equilibrium within a hydrogen bond network formed to bound phenols in the active site of ketosteroid isomerase. We systematically varied the(More)
A longstanding proposal in enzymology is that enzymes are electrostatically and geometrically complementary to the transition states of the reactions they catalyze and that this complementarity contributes to catalysis. Experimental evaluation of this contribution, however, has been difficult. We have systematically dissected the potential contribution to(More)
The thousands of enzyme structures solved to date have consistently revealed that biological catalysis occurs within sequestered pockets containing complex interdigitations of polar and hydrophobic groups and from which water molecules are displaced upon substrate binding.1 This chemical complexity has sparked considerable controversy regarding the(More)
The structure of an AKAP docked to the dimerization/docking (D/D) domain of the type II (RIIalpha) isoform of protein kinase A (PKA) has been well characterized, but there currently is no detailed structural information of an AKAP docked to the type I (RIalpha) isoform. Dual-specific AKAP2 (D-AKAP2) binds in the nanomolar range to both isoforms and provided(More)
Hydrogen bond networks are key elements of biological structure and function. Nevertheless, their structural properties are challenging to assess within complex macromolecules. Hydrogen-bonded protons are not observed in the vast majority of protein X-ray structures, and static crystallographic models provide limited information regarding the dynamical(More)