Structural biology: The amino acid antiporter

Nature China ◽  
2009 ◽  
Author(s):  
Felix Cheung
Keyword(s):  
Amino Acid ◽  
Structural Biology

scholarly journals Crystal Structure and Structural Mechanism of a Novel Anti-Human Immunodeficiency Virus and d-Amino Acid-Containing Chemokine

2007 ◽  
Vol 81 (20) ◽  
pp. 11489-11498 ◽  
Author(s):  
Dongxiang Liu ◽  
Navid Madani ◽  
Ying Li ◽  
Rong Cao ◽  
Won-Tak Choi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Structural Biology ◽  
Chemokine Receptors ◽  
Structural Basis ◽  
Receptor Selectivity ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Chemokines and their receptors play important roles in normal physiological functions and the pathogeneses of a wide range of human diseases, including the entry of human immunodeficiency virus type 1 (HIV-1). However, the use of natural chemokines to probe receptor biology or to develop therapeutic drugs is limited by their lack of selectivity and the poor understanding of mechanisms in ligand-receptor recognition. We addressed these issues by combining chemical and structural biology in research into molecular recognition and inhibitor design. Specifically, the concepts of chemical biology were used to develop synthetically and modularly modified (SMM) chemokines that are unnatural and yet have properties improved over those of natural chemokines in terms of receptor selectivity, affinity, and the ability to explore receptor functions. This was followed by using structural biology to determine the structural basis for synthetically perturbed ligand-receptor selectivity. As a proof-of-principle for this combined chemical and structural-biology approach, we report a novel d-amino acid-containing SMM-chemokine designed based on the natural chemokine called viral macrophage inflammatory protein II (vMIP-II). The incorporation of unnatural d-amino acids enhanced the affinity of this molecule for CXCR4 but significantly diminished that for CCR5 or CCR2, thus yielding much more selective recognition of CXCR4 than wild-type vMIP-II. This d-amino acid-containing chemokine also showed more potent and specific inhibitory activity against HIV-1 entry via CXCR4 than natural chemokines. Furthermore, the high-resolution crystal structure of this d-amino acid-containing chemokine and a molecular-modeling study of its complex with CXCR4 provided the structure-based mechanism for the selective interaction between the ligand and chemokine receptors and the potent anti-HIV activity of d-amino acid-containing chemokines.

scholarly journals Amino acid physical chemistry furnishes a two-dimensional basis set for computational structural biology

2017 ◽  
Vol 73 (a1) ◽  
pp. a299-a299
Author(s):  
Charles W. Carter ◽  
Richard Wolfenden ◽  
Celia A. Schiffer ◽  
Ronald Swanstrom ◽  
Marc Potempa
Keyword(s):  
Physical Chemistry ◽  
Amino Acid ◽  
Structural Biology ◽  
Basis Set ◽  
Two Dimensional ◽  
Computational Structural Biology

scholarly journals Rush Hour of LATs towards Their Transport Cycle

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 602
Author(s):  
Adrià Nicolàs-Aragó ◽  
Joana Fort ◽  
Manuel Palacín ◽  
Ekaitz Errasti-Murugarren
Keyword(s):  
Plasma Membrane ◽  
Amino Acid ◽  
Structural Biology ◽  
Amino Acid Transporters ◽  
Functional Information ◽  
Cationic Amino Acid ◽  
Substrate Interaction ◽  
Transport Cycle ◽  
Remote Homologs ◽  
Molecular Bases

The mammalian SLC7 family comprises the L-amino acid transporters (LATs) and the cationic amino acid transporters (CATs). The relevance of these transporters is highlighted by their involvement in several human pathologies, including inherited rare diseases and acquired diseases, such as cancer. In the last four years, several crystal or cryo-EM structures of LATs and CATs have been solved. These structures have started to fill our knowledge gap that previously was based on the structural biology of remote homologs of the amino acid–polyamine–organocation (APC) transporters. This review recovers this structural and functional information to start generating the molecular bases of the transport cycle of LATs. Special attention is given to the known transporter conformations within the transport cycle and the molecular bases for substrate interaction and translocation, including the asymmetric interaction of substrates at both sides of the plasma membrane.

scholarly journals Challenges in the computational design of proteins

2009 ◽  
Vol 6 (suppl_4) ◽  
Author(s):  
María Suárez ◽  
Alfonso Jaramillo
Keyword(s):  
Amino Acid ◽  
Structural Biology ◽  
Protein Design ◽  
Current Knowledge ◽  
Computational Design ◽  
Amino Acid Sequences ◽  
Computational Protein Design ◽  
Energy Functions ◽  
Physical Description ◽  
Atomic Interactions

Protein design has many applications not only in biotechnology but also in basic science. It uses our current knowledge in structural biology to predict, by computer simulations, an amino acid sequence that would produce a protein with targeted properties. As in other examples of synthetic biology, this approach allows the testing of many hypotheses in biology. The recent development of automated computational methods to design proteins has enabled proteins to be designed that are very different from any known ones. Moreover, some of those methods mostly rely on a physical description of atomic interactions, which allows the designed sequences not to be biased towards known proteins. In this paper, we will describe the use of energy functions in computational protein design, the use of atomic models to evaluate the free energy in the unfolded and folded states, the exploration and optimization of amino acid sequences, the problem of negative design and the design of biomolecular function. We will also consider its use together with the experimental techniques such as directed evolution. We will end by discussing the challenges ahead in computational protein design and some of their future applications.

Vascular Plant Lignification: Biochemical/Structural Biology Considerations of Upstream Aromatic Amino Acid and Monolignol Pathways

2010 ◽  
pp. 541-604 ◽  
Author(s):  
Dhrubojyoti D. Laskar ◽  
Oliver R.A. Corea ◽  
Ann M. Patten ◽  
ChulHee Kang ◽  
Laurence B. Davin ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structural Biology ◽  
Aromatic Amino Acid ◽  
Vascular Plant

Amino Acid-Selective Segmental Isotope Labeling of Multidomain Proteins for Structural Biology

ChemBioChem ◽  
2013 ◽  
Vol 14 (4) ◽  
pp. 457-466 ◽  
Author(s):  
Erich Michel ◽  
Lenka Skrisovska ◽  
Kurt Wüthrich ◽  
Frédéric H.-T. Allain
Keyword(s):  
Amino Acid ◽  
Structural Biology ◽  
Isotope Labeling ◽  
Multidomain Proteins ◽  
Segmental Isotope Labeling

scholarly journals Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Vladimir Frecer ◽  
Giancarlo Iarossi ◽  
Anna Paola Salvetti ◽  
Paolo Enrico Maltese ◽  
Giulia Delledonne ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structural Biology ◽  
Tertiary Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Macular Dystrophy ◽  
Vitelliform Macular Dystrophy ◽  
Best Vitelliform Macular Dystrophy ◽  
Potential Pathogenicity ◽  
Computational Structural Biology

Abstract Background Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium. Methods Here we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands. Results Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants. Conclusions Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.

The staining pattern of the tropomyosin sequence is displayed in a new paracrystal

1986 ◽  
Vol 44 ◽  
pp. 150-151
Author(s):  
M.K. Lamvik ◽  
L.L. Klatt
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Staining Pattern ◽  
Banding Patterns ◽  
Mass Thickness ◽  
New Form

Tropomyosin paracrystals have been used extensively as test specimens and magnification standards due to their clear periodic banding patterns. The paracrystal type discovered by Ohtsuki1 has been of particular interest as a test of unstained specimens because of alternating bands that differ by 50% in mass thickness. While producing specimens of this type, we came across a new paracrystal form. Since this new form displays aligned tropomyosin molecules without the overlaps that are characteristic of the Ohtsuki-type paracrystal, it presents a staining pattern that corresponds to the amino acid sequence of the molecule.

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