Tuning coordination chemistry through the second sphere in designed metallocoiled coils

Abstract

The hydration state of designed metal binding sites in coiled coils can be tuned by terminal second sphere residues.

How the Local Environment of Functional Sites Regulates Protein Function

“…158−161 This is underscored by recent trends in metalloprotein design, focusing on modifying the second-shell interactions to fine-tune the metal-binding affinity 104 and control the number of metal-bound water molecules in designed metallocoiled-coils. 162 Computational design of enzymes employing a catalytic lysine, 43 cysteine, 163 or serine 44 further supports the aforementioned physicochemical principles. These studies indicate that successful computational design of enzymes with catalytic dyads/triads generally requires constraining catalytic residues via extensive hydrogenbonding/packing interactions in a relatively buried and rigid local environment.…”

“…We show how proteins employ these key principles to organize the local environment around functional Cys residues and how this environment regulates the Cys reactivity as well as metal ion toxicity and release. Knowing the physicochemical principles governing formation of optimal local environments around the functional sites would help to elucidate how the protein matrix controls the metal-binding site , and guide the design of functional metalloproteins, enzymes, , and biosensors or rational drug design. − This is underscored by recent trends in metalloprotein design, focusing on modifying the second-shell interactions to fine-tune the metal-binding affinity and control the number of metal-bound water molecules in designed metallocoiled-coils . Computational design of enzymes employing a catalytic lysine, cysteine, or serine further supports the aforementioned physicochemical principles.…”

De novodesigned coiled coils as scaffolds for lanthanides, including novel imaging agents with a twist

“…95,[120][121][122][123][124] Using these principles, steric changes to the secondary coordination sphere have also been used to tune the hydration state of bound lanthanide ions. 125 The starting point was the binding site within MB1-1, located towards the N-terminus of the coiled coil, which generates a highly hydrated lanthanide site, Tb(OH 2 ) 3 (MB1-1) 3 . MB1-1, contains a non-coordinating terminal isoleucine (Ile) layer directly above the Asn/Asp binding site residues (in the a position of the first heptad) and it was the identity of this residue that was systematically altered to Ala, phenylalanine (Phe), tyrosine (Tyr) and Trp (MB1-1(2X), Figure 5, Table 3).…”

Unravelling the Structure of the Tetrahedral Metal-Binding Site in METP3 through an Experimental and Computational Approach

“…Several fundamental aspects of metal cofactor assembly and functions have been clarified by studying natural metalloproteins and their site-directed mutants [ 11 , 12 ]. In addition, numerous model systems have been developed by engineering metal-binding sites into artificial protein scaffolds [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. They represent useful platforms for structure–activity relationship studies, allowing for a fast and easy screening of several mutants [ 21 , 22 ].…”