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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	Deciphering the synthetic and refolding strategy of a cysteine-rich domain in the tumor necrosis factor receptor (TNF-R) for racemic crystallography analysis and D-peptide ligand discovery Alexander J. Lander , Yifu Kong , Yi Jin , Chuanliu Wu , Louis Y. P. Luk Acs Bio & Med Chem Au DOI: 10.1021/acsbiomedchemau.3c00060 Diamond Proposal Number(s): [20147] Open Access Show Abstract ▼ Abstract: Many cell-surface receptors are promising targets for chemical synthesis because of their critical roles in disease development. This synthetic approach enables investigations by racemic protein crystallography and ligand discovery by mirror-image methodologies. However, due to their complex nature, the chemical synthesis of a receptor can be a significant challenge. Here, we describe the chemical synthesis and folding of a central, cysteine-rich domain of the cell-surface receptor tumor necrosis factor 1 which is integral to binding of the cytokine TNF-α, namely, TNFR-1 CRD2. Racemic protein crystallography at 1.4 Å confirmed that the native binding conformation was preserved, and TNFR-1 CRD2 maintained its capacity to bind to TNF-α (KD ≈ 7 nM). Encouraged by this discovery, we carried out mirror-image phage display using the enantiomeric receptor mimic and identified a d-peptide ligand for TNFR-1 CRD2 (KD = 1 μM). This work demonstrated that cysteine-rich domains, including the central domains, can be chemically synthesized and used as mimics for investigations.	Dec 2023
I04-Macromolecular Crystallography	Structure of the D-cycloserine-resistant variant D322N of alanine racemase from Mycobacterium tuberculosis Cesira De Chiara , Gareth A. Prosser , Roksana Ogrodowicz , Luiz P. S. De Carvalho Acs Bio & Med Chem Au 5 DOI: 10.1021/acsbiomedchemau.2c00074 Diamond Proposal Number(s): [13775, 18566] Open Access Show Abstract ▼ Abstract: Alanine racemase (Alr) is a pyridoxal 5′-phosphate-dependent enzyme that catalyzes the racemization of l-alanine to d-alanine. Alr is one of the two targets of the broad-spectrum antibiotic d-cycloserine (DCS), a structural analogue of d-alanine. Despite being an essential component of regimens used to treat multi- and extensively drug-resistant tuberculosis for almost seven decades, resistance to DCS has not been observed in patients. We previously demonstrated that DCS evades resistance due to an ultralow rate of emergence of mutations. Yet, we identified a single polymorphism (converting Asp322 to Asn) in the alr gene, which arose in 8 out of 11 independent variants identified and that confers resistance. Here, we present the crystal structure of the Alr variant D322N in both the free and DCS-inactivated forms and the characterization of its DCS inactivation mechanism by UV–visible and fluorescence spectroscopy. Comparison of these results with those obtained with wild-type Alr reveals the structural basis of the 240-fold reduced inhibition observed in Alr D322N.	Mar 2023

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